1) Thirty-eight cases of serious adverse events (24 hematologic, 4 cardiovascular and 10 miscellaneous events) associated with quinine use for the treatment of night time leg cramps have been submitted to the FDA's Adverse Event Reporting System (AERS) from April 2005 to October 2008. Of the 24 hematologic cases, median time to onset of adverse events after starting quinine therapy was 13.5 days. Twenty-one patients developed thrombocytopenia (median platelet count: 4500 cells/microliter) with 4 patients developing thrombotic thrombocytopenic purpura (n=2) or idiopathic thrombocytopenic purpura (n=2). Most patients recovered with the discontinuation of quinine therapy; however, 2 deaths were reported (US Food and Drug Administration, 2010).

a) Nausea and vomiting are common side effects of quinine (Tiliakos & Waites, 1981).

a) Nausea has been reported following quinine overdose (Vusirikala et al, 2005).
b) Persistent vomiting has occurred within 2 hours of toxic ingestions (Nordt & Clark, 1998).

a) Hepatotoxicity with therapeutic quinine use has been reported (Perez et al, 1994) and has occurred within 24 hours of initiation of a quinine dose (Farver & Lavin, 1999), although onset generally occurs after 2 weeks of therapy. On discontinuance of quinine, liver enzyme values have returned to normal.

a) Hemolytic uremic syndrome (HUS) has occasionally been reported as an adverse effect of quinine therapy. In these cases, the immune-mediated nature of the blood dyscrasia is specific to quinine. The presence of quinine-dependent antibodies to red cells, granulocytes or platelets has been demonstrated in some cases. There appears to be no correlation between the type and specificity of antibody and severity of renal failure (McDonald et al, 1997).
b) CASE REPORT: HUS was reported in a 46-year-old woman after a single dose of 260 mg quinine (Hagley et al, 1992).
c) CASE REPORT: Following a single 300 mg dose of quinine, a 57-year-old woman presented with a 4 day history of abdominal pain, nausea, diarrhea, bruising and a transient morbilliform rash. Acute renal failure, hemolysis, and evidence of DIC were seen on laboratory data. The patient's serum reacted with normal red cells in an indirect antiglobulin test in the presence of quinine. A diagnosis of HUS was made. The patient recovered following 6 plasma exchanges, supportive hemodialysis and steroid therapy (McDonald et al, 1997).
d) CASE REPORT: A 78-year-old woman developed acute renal failure, progressive coagulopathy, thrombocytopenia, and hemolysis with red blood cell fragmentation several hours after ingesting 150 mg of quinine for treatment of leg cramps. Laboratory analysis showed a serum creatinine of 0.58 mmol/L, elevated LDH and bilirubin serum levels, and a low haptoglobin concentration which is consistent with hemolytic-uremic syndrome. The patient gradually recovered following treatment with plasma exchange, corticosteroids, and hemodialysis, although the serum concentration continued to remain elevated at 0.17 mmol/L two months post ingestion (Morton, 2002).

a) Quinine-induced hemolysis and renal failure, due to acute interstitial nephritis, has been reported (Pawar et al, 1994).

a) A 21-year-old woman ingested 90 g of quinine as a single-dose in her eighth-week of pregnancy to induce abortion. The patient subsequently became drowsy, with dark red urine which was positive for occult blood and albumin. She became oliguric with blood urea climbing to 208 g/dL. Platelet count was reported as 43,000/cu mm; 24 hours after ingestion the patient had a seizure. Therapy with diuretics, blood transfusion and hemodialysis resulted in improvement of her condition with hospital discharge at 37 days (Notelovitz et al, 1970).

a) Arterial blood gas analysis has revealed severe mixed respiratory and metabolic acidosis in a patient with seizures and hypotension after an overdose of 9 grams quinine (Pearson, 1998).

a) HYPOPROTHROMBINEMIA has been reported after quinine overdose (Goldenberg & Wexler, 1988).

a) Hemolytic anemia may occur, particularly in patients with glucose-6-phosphate-dehydrogenase deficiency.

a) Immune-mediated pancytopenia and coagulopathy may occur at therapeutic doses of quinine (Schmitt & Tomford, 1994). This may be associated with renal failure and the hemolytic uremic syndrome (Morton, 2002; Blayney, 1992; Story et al, 1994).
b) Profound thrombocytopenia and neutropenia have been reported in a 40-year-old woman, in addition to menorrhagia, 2 days after starting quinine 300 mg every 6 hours as needed. Platelet-associated antibodies and neutrophil antibodies were detected. Bone marrow aspirate was reported to be normal. Five days after discontinuing quinine, WBC and platelet counts returned to normal (Chuah & Denaro, 2000).

a) Antibodies to platelets, red blood cells, T lymphocytes and neutrophils have been associated with the development of the hemolytic uremic syndrome following quinine use (Stroncek et al, 1992; Aster, 1993; Maguire et al, 1993; Hagley et al, 1992).

a) SUMMARY: Quinine-induced thrombocytopenia appears to be immune mediated. In some patients, the events have been life-threatening or fatal. Cases of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have developed. Thrombocytopenia usually resolves within a week of quinine discontinuation, but is likely to reoccur with the administration of quinine from any source (Prod Info QUALAQUIN(R) oral capsules, 2010).
b) FDA WARNING: In July 2010, the Food and Drug Administration (FDA), announced that due to continued reports of serious side effects in patients using quinine for the "off-label" treatment of night time leg cramps, warned against the use of quinine because of the risk for serious and life-threatening blood-related (ie, thrombocytopenia) reactions. Other adverse events include hemolytic-uremia syndrome/thrombotic thrombocytopenic purpura which can produce permanent kidney damage. The FDA recommends that patients taking quinine for night time leg cramps should discuss other treatment options with a healthcare professional (US Food and Drug Administration, 2010).
c) CASE REPORT/FATALITY: A 70-year-old man was admitted to the ED with shortness of breath and hemoptysis for 24 hours. Of note, the patient had a prior history of quinine-induced thrombocytopenia after a short course of quinine, which responded to prednisone and immunoglobulin. Five days prior to the current admission, the patient had been prescribed quinine (300 mg daily) for leg cramps without knowing the patient's history (ie, no prior medical records available and the patient was a poor historian). He was immediately started on high-flow oxygen to maintain a pulse oximetry of 88%. An initial chest x-ray showed evidence of bilateral pulmonary hemorrhage. Petechiae and ecchymosis were observed over his limbs and he had a platelet count of less than 10 x E(9)/L. A platelet transfusion (4 units) was administered along with prednisone. Immunoglobulin was added after the patient failed to improve. Despite various interventions, the patient developed increased oxygen requirements and died. Although quinine-induced disseminated intravascular coagulation was present, there were no signs of thrombotic thrombocytopenia purpura and hemolytic uremic syndrome (Samaranayake & Yap, 2014).
d) CASE REPORT: A 57-year-old presented to the ED with petechiae and thrombocytopenia (platelet count, 2 x 10(9)/L). Abundant megakaryocytes were seen in a bone marrow aspirate which was consistent with increased peripheral destruction of platelets via quinine-associated immune thrombocytopenia. Laboratory data confirmed therapeutic serum quinine levels, even though the patient denied quinine use. The authors report a Munchausen's syndrome in this patient (Abraham & Whitehead, 1998).

a) CASE REPORT: A 78-year-old woman developed disseminated intravascular coagulation (DIC) several hours after ingesting 150 mg of quinine for treatment of leg cramps. The coagulopathy resolved within 48 hours postingestion (Morton, 2002).

a) Photosensitivity may be seen after therapeutic quinine ingestion (Ljunggren et al, 1992; Ferguson et al, 1987; Okun et al, 1994; Dawson, 1995; Ljunggren et al, 1992; Wagner et al, 1994).

a) Contact dermatitis has been reported after topical application (Tapadinhas et al, 1994) (Valseechi et al, 1994).

a) Severe cutaneous vasculitis developed in a 60-year-old woman 3 weeks after beginning therapy with quinine sulfate (Price et al, 1992).

a) Therapeutic usage of quinine has resulted in severe hypoglycemia (White et al, 1983) Harets et al, 1984) (Okitolonda et al, 1987; Limburg et al, 1993).
b) CASE SERIES: A recent study in 76 children who received intravenous quinine for falciparum malaria did not find any association between quinine and hypoglycemia (Taylor et al, 1988).

a) Severe hypoglycemia has been reported following a quinine overdose (Wenstone et al, 1989).

a) Therapeutic quinine use was associated with a positive lupus anticoagulant test in one study (Bird et al, 1995).

a) A variant form of quinine toxicity, with hypersensitivity mimicking septic shock, has been reported. Within 2 hours of a therapeutic quinine dose, a patient presented to the ED with sudden onset of fever, rigors, and back pain followed within hours by hypotension, metabolic acidosis, and disseminated intravascular coagulation. All cultures were reported to be negative. Within 24 to 36 hours all symptoms abated. This sequence occurred twice; both times it was preceded by a quinine dose 2 hours earlier. No further episodes occurred after stopping quinine (Schattner, 1998).

a) Following an overdose, onset of symptoms of oculotoxicity may vary from a few hours to a day or more (S Sweetman , 1999). In addition to cinchonism, quinine is thought to have either an ischemic action on the retinal vasculature or a direct toxic effect on the retina, causing constricted visual fields that can progress to blindness with dilated nonreactive pupils (Brinton et al, 1980; Dyson & Proudfoot, 1985; Nordt & Clark, 1998; Barrett & Solano, 2002).
b) Central vision usually recovers first. Complete recovery of vision may take several months; pupils may remain dilated after recovery of vision (Wolf et al, 1992). Permanent visual deficits may remain (Prod Info QUALAQUIN(R) oral capsules, 2008).
c) CASE REPORT: Visual function tests following quinine overdose in a 19-year-old girl suggest that quinine exerts a direct effect on the cells of the outer retina and pigment epithelium, as well as on the ganglion cells (Moloney et al, 1987).
d) CASE SERIES: In a series of 165 patients overdosing on quinine, 70 (42%) developed visual symptoms 2 to 24 hours following ingestion. Of these patients, 39 (56%) subsequently complained of total blindness while 31 (44%) developed blurring of vision only.
e) CASE SERIES: In a case series of 96 patients with quinine intoxication, visual toxicity developed in only 1 (3%) of 37 patients with reported ingestions of less than 1 gram compared with 80% of the patients with reported ingestions of more than 5 g (Langford et al, 2003)
f) CASE REPORT: Bilateral loss of vision, with dilated and nonreactive pupils, occurred in a 26-year-old man following ingestion of 5 g quinine and an unknown quantity of alcohol (Drake WM & Hiorns MP, 1994). The individual had been taking 300 mg quinine nightly for several years. The peak serum quinine level was 11 mg/L approximately 16 hours after ingestion.
g) Plasma concentrations associated with the visual deficits usually exceed 15 mcg/mL in less than 10 hours postingestion and greater than 10 mcg/mL after 10 hours. However, plasma concentrations appear to be inadequate to predict the type of visual disturbance.
h) CASE SERIES: Bilateral stellate ganglion block was initiated in 34 patients with impaired visual acuity or blindness, however, response was poor with improvement of symptoms appearing in only 4 cases.
i) Blindness following quinine overdose may be delayed in onset for more than 12 hours. Visual function may return entirely or partially without use of modalities such as hemoperfusion or hemodialysis or stellate ganglion block (Smilkstein et al, 1987; Pearson, 1998).
j) CASE REPORT: A 57-year-old man presented with confusion and bilateral blindness approximately 36 hours after ingesting approximately 7.2 g quinine sulfate (equivalent to 6 g quinine base) with an unknown amount of alcohol. The patient's past medical history included surgery on the left eye, 19 years ago, due to prolapse of the iris secondary to a traffic accident. Physical examination showed bilateral dilation and absent light reflexes. Visual acuity was reduced to light perception only. With supportive care, the patient's central vision partially returned, however visual field defects continued to persist six weeks after hospital discharge (Prasad et al, 2003). It is believed that methanol did not play a role in this patient's blindness because metabolic acidosis, a common occurrence following methanol intoxication, was not present.
k) Complete blindness occurred in a 55-year-old woman 7 days after ingesting an unknown amount of quinine (Taylor, 2004).
l) CASE REPORT: A 39-year-old woman presented with ocular toxicity (reduced visual acuity, dilated, sluggish pupils, and retinal arterial attenuation), 40 hours after taking 28 quinine sulfate tablets (300 mg each). She was treated with nimodipine (60 mg for 6 days), clonidine infusion (300 mcg/24 hours), and stellate ganglion block (SGB) (ropivacaine 1% 10 mL). Since the left eye was amblyopic, it was difficult to quantify the effect of treatment; however, the right visual acuity in the right eye improved from the ability to detect hand motions to 6/12 uncorrected and 9/12 with pinhole correction by the 7th day after admission. The right eye had impaired color vision and severely constricted visual field (Vusirikala et al, 2005).

a) CASE REPORT: A patient developed blindness after receiving his second dose of intravenous quinine. Vision began to improve 6 hours later, and the following morning vision had returned to normal. The patient's quinine clearance was reduced, and vision began to return when total serum quinine levels peaked. The return of vision was associated with an increase in alpha1-acid glycoprotein levels (which is an acute phase reactant that rises as part of the systemic inflammatory reaction associated with malaria and also binds free quinine), resulting in a reduced fraction of unbound quinine (Di Perri et al, 2002).

a) Transient TINNITUS and bilateral nerve deafness have been observed after overdose (Langford et al, 2003; Lincoff, 1955; Braveman et al, 1948; Nordt & Clark, 1998).

a) CASE REPORT: DEAFNESS and mutism occurred in a 14-year-old who overdosed on approximately 6.5 to 7.8 g of quinine sulfate. Symptoms lasted approximately 3 days (Schonwald & Shannon, 1991).
b) CASE SERIES: In a case series of 96 patients with quinine intoxication, tinnitus and other auditory complaints developed in 17% of the patients with reported ingestions of less than 1 gram compared with 80% of the patients with reported ingestions of more than 5 g (Langford et al, 2003).
c) Positional abnormalities have been documented at subtherapeutic quinine concentrations that may occur from drinking 1.6 L/day of tonic water (Jung et al, 1993).

a) Dose-dependent hearing impairment was observed in volunteers taking therapeutic doses of quinine. No differences were observed when the drug was administered orally or intravenously (Paintaud et al, 1993).
b) Hearing loss is typically reversible at therapeutic doses and occurs in 20% of patients taking prolonged courses of 200 to 300 mg daily. Sensorineural hearing loss affects high frequencies initially. By the time losses at conversational frequencies are noted, the hearing loss may be irreversible (Jung et al, 1993).

a) Ventricular tachycardia, torsade de pointes, and cardiac arrest were reported in a patient who ingested 600 mg of quinine daily for 7 days in combination with mefloquine (Langford et al, 2003).

a) Sinus tachycardia and minor ECG changes appear to be the most common cardiovascular effects following overdose. Toxic ECG manifestations include prolongation of PR, QRS and QT intervals, ST depression, and T wave inversion. QT prolongation greater than 50% suggests toxicity. Severe poisoning may result in conduction abnormalities and ventricular dysrhythmias (Vusirikala et al, 2005).
b) CONDUCTION DEPRESSION: Sinoatrial, atrioventricular, and His-ventricular conduction delays are common. Ventricular tachycardia and ventricular fibrillation occur with severe toxicity.
c) Sinus bradycardia may occur but anticholinergic effects usually predominate, resulting in sinus tachycardia.
d) Cardiovascular effects are similar to quinidine but less common. Deaths from dysrhythmias do occur (Dyson & Proudfoot, 1985; Goldenberg & Wexler, 1988).
e) ONSET: Cardiotoxicity typically appears within 8 hours following ingestion of quinine. Cardiotoxicity delayed until 25 hours after ingestion has been reported (Bodenhamer & Smilkstein, 1993). Prolonged QRS has been reported in a patient who presented approximately 1 hr post-ingestion of 9 grams quinine (Pearson, 1998).
f) CASE REPORT: Following ingestion of 5.5 grams of quinine, a 51-year-old woman experienced a normal sinus rhythm on ECG with a QRS interval of 0.109 sec and a prolonged corrected QT interval of 0.533 sec. After charcoal administration, a second ECG 3 hours later showed the corrected QT interval to remain prolonged at 0.509 sec, and 30 hr later ECG still showed a prolonged corrected QT interval of 0.520 sec. The patient left the hospital against medical advice 36 hr post ingestion (Nordt & Clark, 1998).
g) CASE REPORT: Following an overdose of quinine of 9.75 grams, a 32-year-old man presented to the ED. A wide complex tachycardia associated with hypotension was noted, which persisted in spite of pacing, cardioversion, fluids and vasopressors. The patient died approximately 64 hours after the ingestion (Morrison et al, 2003; Morrison et al, 2001).

a) CASE REPORT: Asystolic cardiac arrest was reported in a 16-month-old who ingested 600 mg of quinine. Several episodes occurred over a 5 hour period (Hla et al, 1992).

a) Quinine syncope is attributed to transient torsade de pointes (Swiryn & Kimm, 1983).
b) Occurrence of syncope or sudden death correlates with QT prolongation but does not correlate with toxic quinine levels or other ECG abnormalities (Bauman et al, 1984).

a) Hypotension occurs from alpha receptor-blockade and depressed myocardial contractility. Heart failure may result (Goldenberg & Wexler, 1988). Within a few hours of ingestion of 9 grams quinine, an adult experienced a drop in blood pressure to 85/65 mmHg; he was resuscitated with 3500 mL intravenous fluids (Pearson, 1998).
b) CASE REPORT: A 32-year-old man developed hypotension (99/45 mmHg) accompanied by wide complex tachycardia after ingesting 30 325-mg quinine tablets (a total of 9.75 g). Despite decontamination with activated charcoal and administration of fluids, vasopressors, cardioversion, and pacing, the patient died approximately 64 hours postingestion (Morrison et al, 2003).

a) Massive overdose of quinine has resulted in respiratory depression (Bateman & Dyson, 1986).

a) CASE REPORT: A 45-year-old woman, with a history of rheumatoid arthritis, presented with dyspnea, wheezing, a dry nonproductive cough, orthopnea, fever, chills, and pleuritic chest discomfort approximately 45 minutes after ingesting a single 325-mg dose of quinine for treatment of nocturnal leg cramps. Physical examination revealed diminished bilateral breath sounds with diffuse expiratory wheezing and basilar crackles, and pulse oximetry showed an oxygen saturation of 79%. A chest X-ray showed bilateral diffuse alveolar infiltrates, consistent with non-cardiogenic pulmonary edema. The patient recovered following administration of 100% oxygen, nebulized albuterol, and intravenous administration of corticosteroids (Krantz et al, 2002).

a) Adult respiratory distress syndrome (ARDS) was reported in a fatal case (Wenstone et al, 1989).

a) CASE REPORT/FATALITY: A 70-year-old man was admitted to the ED with shortness of breath and hemoptysis for 24 hours. Of note, the patient had a prior history of quinine-induced thrombocytopenia after a short course of quinine, which responded to prednisone and immunoglobulin. Five days prior to the current admission, the patient had been prescribed quinine (300 mg daily) for leg cramps without knowing the patient's history (ie, no prior medical records available and the patient was a poor historian). He was immediately started on high-flow oxygen to maintain a pulse oximetry of 88%. An initial chest x-ray showed evidence of bilateral pulmonary hemorrhage. Petechiae and ecchymosis were observed over his limbs and he had a platelet count of less than 10 x E(9)/L. A platelet transfusion (4 units) was administered along with prednisone. Immunoglobulin was added after the patient failed to improve. Despite various interventions, the patient developed increased oxygen requirements and died. Although quinine-induced disseminated intravascular coagulation was present, there were no signs of thrombotic thrombocytopenia purpura and hemolytic uremic syndrome (Samaranayake & Yap, 2014).

a) Coma and cinchonism may occur with quinine (Bateman & Dyson, 1986; Valman & White, 1977; Friedman, 1980; Garrod & Judson, 1981).

a) Quinine overdose may produce grand mal seizures (Valman & White, 1977; Friedman, 1980; Garrod & Judson, 1981; Pearson, 1998).
b) CHILDREN: Central nervous system toxicity seems to be more marked in children than adults; children frequently present with seizures following an overdose of quinine (Hla et al, 1987; Grattan-Smith et al, 1987).

a) Quinine may produce ataxia (Bateman & Dyson, 1986; Valman & White, 1977; Friedman, 1980; Garrod & Judson, 1981).

a) Quinine overdose may produce paresthesias (Valman & White, 1977; Friedman, 1980; Garrod & Judson, 1981).

a) CASE REPORT: Confusion and delirium occurred in a 57-year-old man after ingesting approximately 7.2 g quinine sulfate (equivalent to 6 g quinine base) and an unknown amount of alcohol (Prasad et al, 2003).

a) Obtain an ECG and institute continuous cardiac monitoring.

1) A 44-year-old man who ingested 6.8 g of quinine sulfate 5 hours before admission, became totally blind 1 hour before admission. Following gastric lavage acid diuresis and bilateral stellate ganglion block some light perception returned.

1) There is no evidence of central nervous system toxicity such as seizures or CNS depression,
2) Acid-base disturbances are corrected,
3) Electrolytes are normal,
4) The electrocardiogram has returned to baseline,
5) And there is no hypoglycemia.

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).

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

a) Multiple dose charcoal has not been shown to affect outcome after quinine overdose. It is recommended in patients with severe toxicity and those with rising levels despite initial decontamination.
b) Lockey & Bateman (1989) demonstrated an increase of oral clearance by 56% and decrease in half-life from 8.23 to 4.55 hours after therapeutic doses of quinine and MDC 50 grams every 4 hours (Lockey & Bateman, 1989).
c) In a study of quinine overdose patients, the same regimen of MDC resulted in a mean half-life of 8.1 hours, compared to 26 hours in previous reports of overdosed patients (Prescott et al, 1989).
d) A half-life of 33 hours prior to charcoal decreased to 10 hours after charcoal administration in a single patient (Prescott et al, 1989).

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

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).

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 .

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).

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).

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).

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):

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).

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).

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).

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).

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).
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).

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

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.

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

a) Blindness usually resolves without treatment. Stellate ganglion block (SGB) has never been proven beneficial in any clinical study and is potentially dangerous. Its use is NOT recommended.
b) Stellate ganglion block is theorized to improve regional blood supply (Valman & White, 1977; Boscoe et al, 1983; Thomas, 1984).
c) Since the primary toxic effect of quinine is direct damage of photoelectric cells, any benefit of stellate block is probably minimal or coincident with spontaneous visual return, and the procedure has serious complications (Boland et al, 1985; Dyson & Proudfoot, 1985).
d) Treatment of quinine overdose including stellate ganglion block had no apparent benefit in a series of 25 patients (Dyson et al, 1985a). This was recently confirmed (Bacon et al, 1988).
e) In one case report, a late presentation of ocular quinine toxicity was managed with a combination of vasodilatory treatments (oral nimodipine, clonidine infusion, and SGB) (Vusirikala et al, 2005).

a) Retinal arterial constriction is often noted with quinine toxicity.
b) Hla et al (1992) treated a case of blindness (16-month-old who ingested 600 mg) with intravenous isosorbide dinitrate. An ophthalmological review 6 weeks post discharge showed full restoration of sight.
c) A 36-year-old man presented with blindness 8 to 10 hours after quinine overdose (Moore et al, 1992). There was some evidence of visual recovery 1 to 2 hours after intravenous nitrates were begun, and he eventually had total visual recovery.

a) In a case of quinine poisoning resulting in bilateral visual loss with retinal arteriolar constriction, fluctuating visual loss suggested an element of vasospasm. The authors chose to use IV nimodipine (0.01 mg/kg/hr) for vasospasm, and IV hydration with 0.9% saline to maintain a central venous pressure of at least 9 mmHg. In addition, IV noradrenaline was administered to maintain a systolic blood pressure of 140 to 180 mmHg. Over the next 24 hours, the patient's vision improved to 6/9 bilaterally and did not deteriorate again. Within 12 hours of the therapy, retinal blood flow was noted to be improved on direct fundoscopy (Barrett & Solano, 2002).

a) 16 YEARS OF AGE OR OLDER: For the treatment of uncomplicated P falciparum malaria, the recommended dose is 648 mg (2 capsules) every 8 hours for 7 days (Prod Info QUALAQUIN(R) oral capsules, 2014)
b) LESS THAN 16 YEARS OF AGE: For the treatment of uncomplicated, chloroquine-resistant malaria, the recommended dose is 10 mg/kg of quinine sulfate orally three times daily for 3 or 7 days. The duration of treatment is dependent on the region where the infection was acquired: 7 days, if the infection was acquired in Southeast Asia; 3 days, if the infection was acquired elsewhere (Centers for Disease Control and Prevention, 2009).

a) An intravenous loading dose of quinine (20 mg/kg) followed by 10 mg/kg every 8 hours has been suggested in children with cerebral malaria (Van der Torn et al, 1998).

a) LEVELS NOT RESULTING IN TOXICITY -
b) TOXIC LEVELS -
c) FATAL LEVELS -

a) 115 mg/kg (RTECS, 2006)