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CREATINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Creatine is a naturally occurring nitrogen compound found primarily in skeletal muscle tissue of many vertebrates. It is produced by the liver and kidneys by the transfer of the guanidine moiety of arginine to glycine which is then methylated to give creatine (Budavari, 1996).

Specific Substances

    1) Creatine monohydrate
    2) N-(aminoiminomethyl)-N-methylglycine
    3) N-amidinosarcosine
    4) N-methyl-N-guanylglycine;
    5) methylglycocyamine
    6) Molecular Formula: C4-H9-N3-O2

Available Forms Sources

    A) FORMS
    1) Creatine is commercially isolated from meat extracts (Budavari, 1996). Creatine monohydrate is a white powder that is odorless and virtually tasteless which dissolves easily in liquids.
    B) SOURCES
    1) The skeletal muscle of most mammals and fish contain creatine. Sources include: herring, beef, pork, salmon, and cod (Clark, 1998). Currently, creatine monohydrate supplements are available through health food and nutritional stores. Creatine may be combined with other nutritional products.
    C) USES
    1) Creatine is known as an ergogenic aid for sports performance which suggests the ability to enhance energy utilization, including energy production, control, and efficiency (Mujika & Padilla, 1997). Athletes at all levels (i.e., includes athletes as young as high school aged) may consider creatine supplementation a safe alternative to anabolic-adrogenic steroids and is widely available for use (Smith & Dahm, 2000).
    a) INCIDENCE - Studies that have attempted to estimate the prevalence of creatine use suggest that it is in the range of 25% to 75% among professional American football players, 40% to 45% among a group of elite Norwegian power athletes aged 17 to 31 years, and 50% among male collegiate athletes at a single institution (Smith & Dahm, 2000).
    b) Consumption of creatine during 2000 by elite athletes, recreational athletes, and teenagers exceeded 2.5 million kilograms in the United States (Sabatini, 2001).
    2) Creatine is touted as a performance-enhancing supplement believed to build muscle mass and increase overall strength and endurance (Clark, 1998; (Strauss, 1998)).
    3) Studies have been conducted to determine the potential benefit of creatine in some diseases including: chronic heart failure (Field, 1996; Gordon, 1996) and mitochondrial cytopathies (Tarnopolsky et al, 1997).
    a) In one small study (n=20 males) of subjects with stable chronic heart failure, creatine supplementation was shown to produce favorable effects on skeletal muscle endurance and metabolism; however, ongoing long-term results regarding symptoms and exercise performance requires further study (Andrews et al, 1998).
    4) During the spring of 1998, the US FDA issued a warning to consumers to consult a physician prior to using creatine supplements, based on a lack of data regarding its long-term safety (O'Donnell, 1998). The FDA is currently monitoring adverse events reported following the use of creatine supplements.

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Creatine is known as an ergogenic aid for sports performance which suggests the ability to enhance energy utilization, including energy production, control, and efficiency. It is marketed as a performance-enhancing supplement believed to build muscle mass and increase overall strength and endurance. Athletes at all levels (i.e., includes athletes as young as high school aged) may consider creatine supplementation a safe alternative to anabolic-androgenic steroids and is widely available for use.
    B) PHARMACOLOGY: Creatine is a naturally occurring nitrogen compound found primarily in skeletal muscle tissue of many vertebrates. It is produced by the liver and kidneys by the transfer of the guanidine moiety of arginine to glycine which is then methylated to produce creatine.
    C) EPIDEMIOLOGY: Creatine is widely available over-the-counter. Use is common, but severe toxicity with creatine is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects are usually mild; serious adverse events are rarely associated with creatine use. Adverse effects include: gastrointestinal effects (ie, nausea, vomiting, diarrhea, abdominal pain), weight gain related to water retention, dehydration, muscle cramps, nervousness, anxiety, headaches, and fatigue.
    2) RARE: Acute renal failure, interstitial nephritis, rhabdomyolysis, venous thrombosis, and anaphylaxis have been rarely reported.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Heat intolerance has been associated with creatine supplement use.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor renal function following a significant acute exposure or chronic use.
    C) Monitor creatine kinase (CK) in patients with muscle pain, tenderness or weakness.
    D) Monitor renal function and urine output in patients with rhabdomyolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is generally not expected after a creatine overdose. In patients with an acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity after an acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Toxicity after an acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been ingested concurrently.
    E) ANTIDOTE
    1) None.
    F) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    G) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dietary supplement ingested by a young child) may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored for symptoms. Patients may be discharged to home, if no symptoms develop.
    3) ADMISSION CRITERIA: Patients with persistent symptoms should be admitted for further treatment.
    4) CONSULT CRITERIA: Contact a medical toxicologist or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    I) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    2) Failure to obtain an adequate history of exposure.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause renal toxicity and/or rhabdomyolysis.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. In a healthy adult, creatine supplementation of 25 g daily for a year (5 times the recommended maintenance daily dose) in addition to intense exercise resulted in the development of acute quadriceps compartment syndrome, rhabdomyolysis, and renal failure. It has been postulated that in the elderly and in individuals with pre-existing renal disease or diabetes, daily doses of more than 2 g or 0.03 g/kg may cause or exacerbate renal dysfunction.
    B) THERAPEUTIC DOSE: Loading dose of up to 20 g daily for 6 to 14 days, followed by a maintenance dose of 2 to 5 g daily.

Clinical Effects

Summary Of Exposure

    A) USES: Creatine is known as an ergogenic aid for sports performance which suggests the ability to enhance energy utilization, including energy production, control, and efficiency. It is marketed as a performance-enhancing supplement believed to build muscle mass and increase overall strength and endurance. Athletes at all levels (i.e., includes athletes as young as high school aged) may consider creatine supplementation a safe alternative to anabolic-androgenic steroids and is widely available for use.
    B) PHARMACOLOGY: Creatine is a naturally occurring nitrogen compound found primarily in skeletal muscle tissue of many vertebrates. It is produced by the liver and kidneys by the transfer of the guanidine moiety of arginine to glycine which is then methylated to produce creatine.
    C) EPIDEMIOLOGY: Creatine is widely available over-the-counter. Use is common, but severe toxicity with creatine is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects are usually mild; serious adverse events are rarely associated with creatine use. Adverse effects include: gastrointestinal effects (ie, nausea, vomiting, diarrhea, abdominal pain), weight gain related to water retention, dehydration, muscle cramps, nervousness, anxiety, headaches, and fatigue.
    2) RARE: Acute renal failure, interstitial nephritis, rhabdomyolysis, venous thrombosis, and anaphylaxis have been rarely reported.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Heat intolerance has been associated with creatine supplement use.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Unpublished anecdotal reports of heat intolerance have been associated with creatine supplement use (Clark, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) At the time of this review, 4 cases of seizures associated with creatine supplementation have been reported to the FDA. Of those cases, only one did not involve the concomitant use of other nutritional products ((Anon, 1998)).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Several reports of headache, nervousness, anxiety, and behavior change (aggression) have been reported with creatine supplementation ((Anon, 1998)). Of the 3 cases, one patient was using creatine alone, while the other two were using multiple supplements.
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue has been reported in 3 cases following creatine supplementation ((Anon, 1998)).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) There have been reports of diarrhea, nausea and vomiting, and abdominal cramps following creatine supplementation (Clark, 1998; O'Donnell, 1998; (Anon, 1998)).
    b) Creatine that has been inadequately dissolved prior to ingestion may cause gastrointestinal discomfort (Greenhaff, 1998).
    c) INCIDENCE: Of 27 (21 were male football players) high school athletes that used creatine supplements, 5 respondents reported either minor gastrointestinal symptoms (e.g., diarrhea, cramps, and loss of appetite) or muscle cramps (Smith & Dahm, 2000).
    d) A prospective study was conducted to evaluate the incidence of gastrointestinal adverse effects in patients taking creatine supplements. Fifty-nine athletes were included in the randomized double-blind placebo-controlled study, and divided into 3 groups: ingestion of creatine 5 g twice daily (n=21), ingestion of creatine 10 g once daily (n=18), and ingestion of a placebo (n=20). Each participant was then asked to record any episodes of gastrointestinal effects that occurred. According to the results of this study, there were no significant differences in the incidences of gastrointestinal adverse effects between the three groups with respect to abdominal pain, heartburn, nausea, vomiting, bloating, belching, stomach upset, or constipation. However, the incidences of diarrhea were significant between the creatine 5 g and creatine 10 g groups (28.6% vs 55.6%, respectively; p<0.05). Diarrhea also occurred more frequently with the creatine 10 g group compared to the placebo group (55.6% vs 35%, respectively, p<0.05) (Ostojic & Ahmetovic, 2008).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) AT RISK - FINDING
    1) WITH THERAPEUTIC USE
    a) Creatine supplementation increases the workload of the kidneys and is generally NOT recommended in individuals with a history of renal dysfunction or potential pre-existing renal disease such as diabetes or the elderly (Pepping, 1999).
    B) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 25-year-old man with a history of glomerulosclerosis with frequent relapsing steroid-responsive nephrotic syndrome, developed an elevated serum creatinine (baseline 103 mmol/L) which peaked at 180 mmol/L following creatine supplementation; no other drugs were taken. The patient had taken an initial dose of 15 grams/day for one week followed by a maintenance dose of 2 grams/day for seven weeks. Serum creatinine was 128 mmol/L one month after discontinuing the supplement (Pritchard & Kalra, 1998)
    1) Greenhaff (1998) has suggested that the 2 grams/day maintenance dose taken by the patient (described by Pritchard & Kalra) would only contain slightly more creatine than would be found in an average meat-eater's diet (Greenhaff, 1998). There is approximately 1 gram of creatine in one large serving of certain meats (herring 6.5 g/kg, beef 5.5 g/kg, pork 5.0 g/kg, salmon 4.5 g/kg, and, cod 3.0 g/kg) (Clark, 1998).
    C) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 18-year-old man presented with a 2-day history of nausea, vomiting, and abdominal pains. His initial blood pressure was 150/90. Interview of the patient revealed that he had been taking creatine supplements at an induction dose of 20 g/day for 5 days, followed by a maintenance dose of 1 g/day for 6 weeks. Laboratory studies demonstrated elevated serum urea and serum creatinine concentrations of 39.98 mmol/L and 201.55 mmol/L, respectively (normal 0 to 36 mmol/L and 44.2 to 106 mmol/L, respectively). Urinalysis revealed proteinuria with a daily protein excretion of 284 mg. A renal biopsy revealed tubular injury with tubular lumina dilation with sloughed epithelial cells, leukocytes and cellular debris in the lumina, indicative of acute tubular necrosis. After discontinuing the creatine supplements for 25 days, the patient's serum creatinine and proteinuria levels normalized and his blood pressure was normal (Taner et al, 2011).
    b) CASE REPORT: A 21-year-old football player, who underwent reconstructive knee surgery following a skiing accident, developed post-operative rhabdomyolysis and acute renal failure. Laboratory studies, obtained on the first post-operative day, revealed a serum creatinine concentration of 1.7 mg/dL and a creatine kinase (CK) of 167,840 units/liter. Urinalysis demonstrated hematuria and myoglobinuria (141 mg/L; normal 0 to 1 mg/L). During the surgery, a tourniquet was applied for 100 minutes. Post-operatively, further questioning of the patient revealed that he was a weight-lifter who had been taking up to 10 g/day of creatine for approximately 6 weeks pre-operatively, but had stopped approximately 3 days prior to surgery. He had also been intermittently taking creatine during the off season from football for the last 6 years. Over the next few days, his serum creatinine continued to increase (2.3 mg/dL on post-operative day 4) associated with a low urine output. With supportive care, including IV fluids and IV diuretics, the patient gradually recovered with improvement in his urine output, and serum creatinine and CK concentrations. The patient was discharged home on post-operative day 7. It is suggested that the rhabdomyolysis and subsequent acute renal failure was associated with the application of the tourniquet intra-operatively resulting in muscle ischemia and exacerbated by his creatine supplement use (Sheth et al, 2006).
    D) INTERSTITIAL NEPHRITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 20-year-old man presented with a 4-day history of nausea, vomiting, and bilateral flank pain, that occurred approximately 4 weeks after he began taking a creatine supplement, 5 g orally four times daily. After symptom onset, the patient stopped taking the creatine and was not on any other medications or dietary supplements. The patient was hypertensive (140/90 mmHg), physical examination revealed dehydration and abdominal tenderness, and a urinalysis demonstrated 4+ protein and 1+ blood. A renal biopsy indicated acute interstitial nephritis and tubular injury. During hospitalization, the patient's blood pressure and serum creatinine concentration increased to 160/100 mmHg and 2.3 mg/dL, respectively, and urinary protein excretion was 472 mg daily. With supportive care, the patient's blood pressure, serum creatinine, and urinalysis normalized (Koshy et al, 1999).
    E) ABNORMAL URINARY PRODUCT
    1) WITH THERAPEUTIC USE
    a) ELEVATED URINARY CREATININE LEVELS: Following creatine conversion to creatinine in the tissue it must be excreted in the urine. Urinary creatinine levels increase during supplementation; levels should decrease upon discontinuation of creatine supplements (Clark, 1998).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BUN INCREASED
    a) RAT STUDY: Oopik et al (1996) found that rats given creatine supplementation over 7 days developed an increase in BUN in both treatment groups (sedentary and exercised rats). The authors were unclear how this mechanism occurred (Oopik et al, 1996).
    2) RENAL FUNCTION ABNORMAL
    a) Edmunds et al (2001) found that Han:Sprague-Dawley (SPRD)-cy rats with cystic kidney disease were given a creatine supplement at a loading dose of 2.0 g/kg of diet for 1 week, followed by 5 weeks with one fifth the dose (dose was typical of human consumption on a body-weight basis) had an alteration in kidney function. The findings indicated that creatine supplementation resulted in greater cyst growth and worsened renal function as evidenced by increased kidney weights, renal fluid contents, cyst scores and serum BUN concentration; and a lower creatinine clearance. The authors concluded that creatine supplements may worsen preexisting cystic renal disease in rats and suggests cautious use in humans at risk for renal disease. Further human studies are indicated (Edmunds et al, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Two patients developed venous thrombosis following therapeutic use of creatine supplements.
    1) The first patient, an 18-year-old man, presented with a 1-week history of a headache associated with vomiting. An MRI of his brain revealed a thrombosis of the superior sagittal sinus, the right transverse sinus, and the right internal jugular vein. There was no family or personal history of venous thromboembolism and comprehensive screening tests, including tests for deficiencies of protein C, protein S, factor V Leiden and antithrombin III, were all negative. Interview of the patient revealed that he had been taking a creatine supplement for the last 3 months prior to presentation and that he was frequently thirsty and drinking more fluids while taking the supplement. Following anticoagulation for 6 months and cessation of creatine-containing products, he recovered without sequelae (Tan et al, 2014)
    2) The second patient, a 31-year-old man, presented with a 5-day history of swelling and pain of his left leg. He was diagnosed with left lower leg deep vein thrombosis. Although there was no personal or family history of venous thromboembolism or any history of recent surgeries or immobilization, the patient had been traveling on a flight lasting 5 hours approximately 3 weeks before presentation and he had been taking creatine supplements up to the time of presentation. Following thrombolytic therapy, anticoagulation treatment for 6 months, and cessation of the creatine supplements, the patient recovered without recurrence of thromboembolic events (Tan et al, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) POTENTIAL INJURY: Rapid increases in skeletal strength could, theoretically, predispose an adolescent to tendon and apophyseal avulsions and disruption of bone growth plates (Pepping, 1999).
    B) COMPARTMENT SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 24-year-old man developed acute compartment syndrome and rhabdomyolysis following intense lower extremity exercise for 3 hours after no exercise for the previous 8 days, and while taking a creatine supplement, 25 g/day (five times the recommended maintenance daily dose) for the past year. He presented with severe bilateral thigh pain that prevented him from walking. Compartment pressures of his anterior, medial, and lateral quadriceps of his right leg were 34, 34, and 32 mmHg, respectively, compared to his left leg of 17, 15, and 15 mmHg, respectively. He underwent emergent bilateral tri-compartment fasciotomies to treat his compartment syndrome, Over the next several days, his hospital course was complicated with worsening of rhabdomyolysis, acute renal failure, cardiomegaly, pulmonary edema, and incomplete right bundle branch block. With aggressive continued supportive care, including urine alkalinization and physical therapy in order to walk independently, the patient's condition improved and he was discharged on hospital day 22 for continued outpatient physical therapy. Six months later, at follow-up, he had achieved approximately 60% of his premorbid quadriceps strength with ongoing aggressive physical therapy (Robinson, 2000).
    C) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Muscle cramps have been reported following creatine supplementation (Clark, 1998; (Anon, 1998)) (Smith & Dahm, 2000).
    b) INCIDENCE: Of 27 (21 were male football players) high school athletes that used creatine supplements, 5 respondents reported either muscle cramps or minor gastrointestinal symptoms (Smith & Dahm, 2000).
    D) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 21-year-old football player, who underwent reconstructive knee surgery following a skiing accident, developed post-operative rhabdomyolysis and acute renal failure. Laboratory studies, obtained on the first post-operative day, revealed a serum creatinine concentration of 1.7 mg/dL and a CK of 167,840 units/liter. Urinalysis demonstrated hematuria and myoglobinuria (141 mg/L; normal 0 to 1 mg/L). During the surgery, a tourniquet was applied for 100 minutes. Post-operatively, further questioning of the patient revealed that he was a weight-lifter who had been taking up to 10 g/day of creatine for approximately 6 weeks preoperatively, but had stopped approximately 3 days prior to surgery. He had also been intermittently taking creatine during the off season from football for the last 6 years. Over the next few days, his serum creatinine continued to increase (2.3 mg/dL on post-operative day 4) associated with a low urine output. With supportive care, including IV fluids and IV diuretics, the patient gradually recovered with improvement in his urine output, and serum creatinine and CK concentrations. The patient was discharged home on post-operative day 7. It is suggested that the rhabdomyolysis and subsequent acute renal failure was associated with the application of the tourniquet intra-operatively resulting in muscle ischemia and exacerbated by his creatine supplement use (Sheth et al, 2006).
    b) CASE REPORT: A 24-year-old man developed acute compartment syndrome and rhabdomyolysis following intense lower extremity exercise for 3 hours after no exercise for the previous 8 days, and while taking creatine supplement, 25 g/day (five times the recommended maintenance daily dose) for the past year. He presented with severe bilateral thigh pain that prevented him from walking. Initial laboratory findings revealed a serum creatinine of 1 mg/dL and a CK of 131,000 units/L. A urinalysis showed proteinuria (3+) and hematuria (4+). He underwent emergent bilateral tri-compartment fasciotomies to treat his compartment syndrome and aggressive hydration with IV fluids and urine alkalinization followed by diuresis to treat his rhabdomyolysis. Over the next several days, his hospital course was complicated with worsening of rhabdomyolysis (CK peak greater than 800,000 units/L), acute renal failure (serum creatinine peak 3.1 mg/dL), cardiomegaly, pulmonary edema, and incomplete right bundle branch block. His rhabdomyolysis resolved following IV fluid administration and urine alkalinization, and with aggressive physical therapy in order to walk independently, the patient's physical condition improved and he was discharged for continued outpatient physical therapy. Six months later, at follow-up, he had achieved approximately 60% of his premorbid quadriceps strength with ongoing aggressive physical therapy (Robinson, 2000).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Symptoms of possible anaphylactoid response have been associated with creatine supplementation. One case included facial rash and eyelid swelling following creatine monohydrate and the second had shortness of breath, facial, lip, tongue and hand swelling along with laryngeal edema following the use of a combination nutritional product which included creatine ((Anon, 1998)).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor renal function following a significant acute exposure or chronic use.
    C) Monitor creatine kinase (CK) in patients with muscle pain, tenderness or weakness.
    D) Monitor renal function and urine output in patients with rhabdomyolysis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor fluid and electrolyte levels as indicated in patients with severe vomiting or diarrhea.
    2) Monitor renal function following acute exposure or significant long-term creatine supplementation. Elevated urinary creatinine levels would be anticipated following initial creatine exposure.
    3) Monitor CK in patients with muscle pain, tenderness or weakness. Monitor renal function and urine output in patients with rhabdomyolysis.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor urinary output in patients as indicated.

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 with persistent symptoms should be admitted for further treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dietary supplement ingested by a young child) may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored for symptoms. Patients may be discharged to home, if no symptoms develop.

Monitoring

    A) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor renal function following a significant acute exposure or chronic use.
    C) Monitor creatine kinase (CK) in patients with muscle pain, tenderness or weakness.
    D) Monitor renal function and urine output in patients with rhabdomyolysis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Toxicity after an acute ingestion is unlikely, and is generally only expected with chronic use. Prehospital gastrointestinal decontamination is generally unnecessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity after an acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    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) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Significant toxicity is generally not expected after a creatine overdose. In patients with an acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    2) Monitor renal function following a significant acute exposure or chronic use.
    3) Monitor creatine phosphokinase in patients with muscle pain, tenderness or weakness.
    4) Monitor renal function and urine output in patients with rhabdomyolysis.
    C) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    D) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. In a healthy adult, creatine supplementation of 25 g daily for a year (5 times the recommended maintenance daily dose) in addition to intense exercise resulted in the development of acute quadriceps compartment syndrome, rhabdomyolysis, and renal failure. It has been postulated that in the elderly and in individuals with pre-existing renal disease or diabetes, daily doses of more than 2 g or 0.03 g/kg may cause or exacerbate renal dysfunction.
    B) THERAPEUTIC DOSE: Loading dose of up to 20 g daily for 6 to 14 days, followed by a maintenance dose of 2 to 5 g daily.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) ATHLETES -
    a) SUMMARY - Sahelian & Tuttle (1996) have suggested that the amount of creatine needed for a loading phase depends on the desired exercise program. Similarly, maintenance dosages are related to exercise level and body weight.
    b) LOADING DOSE - A daily dose of up to 20 grams/day for 6 to 14 days has been suggested (Clark, 1998; Newsholme & Hardy, 1997).
    c) MAINTENANCE - 2 to 5 grams/day has been suggested as a maintenance dose to be taken throughout a training period ((Sahelian, 1996); Clark, 1998).
    2) ELDERLY -
    a) At the time of this review, it has been reported that some elderly individuals consume creatine based on the assumption that it has the ability to limit muscle atrophy ((Strauss, 1998)).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) At the time of this review, no pediatric dose or its safety has been established in this population. Despite the lack of data, the media have reported that creatine supplementation occurs frequently among college and high school athletes (O'Donnell, 1998).

Maximum Tolerated Exposure

    A) SUMMARY
    1) The elderly and individuals with a pre-existing renal disease or diabetes should avoid creatine supplementation due to the potential increased workload of the kidneys; daily doses of 2 grams or 0.03 grams/kilogram may cause or exacerbate renal dysfunction (Pepping, 1999).
    2) CASE REPORT: A 24-year-old man developed acute compartment syndrome and rhabdomyolysis following intense lower extremity exercise for 3 hours after no exercise for the previous 8 days, and while taking creatine supplement, 25 g/day (five times the recommended maintenance daily dose) for the past year. He presented with severe bilateral thigh pain that prevented him from walking. Initial laboratory findings revealed a serum creatinine of 1 mg/dL and a creatine kinase (CK) of 131,000 units/L. A urinalysis showed proteinuria (3+) and hematuria (4+). He underwent emergent bilateral tri-compartment fasciotomies to treat his compartment syndrome and aggressive hydration with IV fluids and urine alkalinization followed by diuresis to treat his rhabdomyolysis. Over the next several days, his hospital course was complicated with worsening of rhabdomyolysis with CK peak greater than 800,000 units/L, acute renal failure (serum creatinine peak 3.1 mg/dL), cardiomegaly, pulmonary edema, and incomplete right bundle branch block. His rhabdomyolysis resolved following IV fluid administration and urine alkalinization, and with aggressive physical therapy in order to walk independently, the patient's physical condition improved and he was discharged for continued outpatient physical therapy. Six months later, at follow-up, he had achieved approximately 60% of his premorbid quadriceps strength with ongoing aggressive physical therapy (Robinson, 2000).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) The average synthesis of creatine by the body is 1 to 2 grams/day (Clark, 1998).
    b) The amount of creatine found in human muscle is approximately 100 to 160 mmol/kg with the upper limit considered to be about 150 to 160 mmol/kg of dry muscle (Mujika & Padilla, 1997).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Creatine is a natural compound that is endogenously synthesized by the liver, pancreas, and kidneys from the amino acids arginine, glycine, and methionine (Mujika & Padilla, 1997). Approximately 95% of the creatine concentration found in the body is contained in skeletal muscle. Other tissues that contain significant amounts of creatine include: heart, spermatozoa, retina, and brain. Creatine is transported in the bloodstream from synthesis sites to utilization sites. Intramuscular phosphocreatine plays a major role in energy metabolism during skeletal muscle contraction, physical exercise, and recovery.

Physicochemical

Molecular Weight

    A) 131.13 (Budavari, 1996)

References

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