- Email: [email protected]
Acute intentional caffeine overdose treated preemptively with hemodialysis
Journal Pre-proofs Acute intentional caffeine overdose treated preemptively with hemodialysis, Benjamin A. Kohl, Kuljit Kaur, Nathan Dincher, Jessica Schumann, Tara Carachilo, Christopher Komurek PII: DOI: Reference:
S0735-6757(19)30630-8 https://doi.org/10.1016/j.ajem.2019.09.018 YAJEM 158528
To appear in:
American Journal of Emergency Medicine
Received Date: Accepted Date:
4 September 2019 24 September 2019
Please cite this article as: B.A. Kohl, K. Kaur, N. Dincher, J. Schumann, T. Carachilo, C. Komurek, Acute intentional caffeine overdose treated preemptively with hemodialysis,, American Journal of Emergency Medicine (2019), doi: https://doi.org/10.1016/j.ajem.2019.09.018
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Inc.
Title: Acute intentional caffeine overdose treated preemptively with hemodialysis Authors: Name 1: Benjamin A. Kohl, MD [corresponding author] Affiliation 1: Division of Critical Care Medicine, Jefferson Northeast Hospital Email 1: [email protected]
Name 2: Kuljit Kaur, DO Affiliation 2: Department of Emergency Medicine, Jefferson Northeast Hospital Email 2: [email protected]
Name 3: Nathan Dincher, DO Affiliation 3: Division of Critical Care Medicine, Jefferson Northeast Hospital Email 3: [email protected]
Name 4: Jessica Schumann, DO Affiliation 4: Department of Emergency Medicine, Jefferson Northeast Hospital Email 4: [email protected]
Name 5: Tara Carachilo, DO Affiliation 5: Department of Emergency Medicine, Jefferson Northeast Hospital Email 5: [email protected]
Name 6: Christopher Komurek, DO Affiliation 6: Department of Emergency Medicine, Jefferson Northeast Hospital Email 6: [email protected]
No external or internal funding was used in the creation of this manuscript. All of the above authors contributed equally in the writing and review of this manuscript.
Abstract Caffeine is the most commonly used central nervous system stimulant. While it has a high LD50 (150-200 mg/kg), when ingested in significant quantity, caffeine can lead to severe and even lethal side effects. Manifestation of toxicity include tachyarrhythmias, seizures, and metabolic derangements which can eventually lead to cardiovascular collapse and death. Studies have shown that lethal doses of caffeine (80-100 ug/mL) can be seen with the ingestion of approximately 10 g of caffeine. Due to the low number of reported cases, there is no consensus on the standard of care for treatment of suspected caffeine overdose. This case details a 39-year-old male who presented to the emergency department (ED) after having ingested 50 g of caffeine. Despite a high dose esmolol infusion, the patient exhibited worsening tachyarrhythmias. Hemodialysis was started empirically given the known amount ingested and ongoing hemodynamic perturbations. Initial pre-dialysis caffeine level was found to be 254 ug/ml. After treatment with two sessions of hemodialysis the patient’s caffeine level decreased dramatically. We believe this is the first case report to demonstrate the success of preemptive hemodialysis, prior to cardiovascular collapse and/or renal failure, in a case of caffeine overdose and should be considered very early in patients presenting with recent toxic ingestion.
Introduction Caffeine (triemethylxanthine, C8H10N4O2) is derived from the purine base, xanthine and is structurally related to adenosine. While there are several target sites of caffeine, the most physiologically important appears to be antagonism at the level of adenosine receptors1. Normally, adenosine mediates downregulation of central nervous system activity through a variety of mechanisms, including the regulation of dopamine. Antagonism of this downregulation results in caffeine’s well-known effects of enhancing cognition and facilitating arousal2. As a reference, a normal cup of coffee typically contains 100-200 mg of caffeine and the Food and Drug Administration considers 400 mg, or 4-5 cups of coffee, per day as a generally safe dose. The effects of caffeine are myriad and the degree to which these effects manifest are largely based on an individual’s sensitivity to methylxanthine. The most commonly reported side effects of caffeine include insomnia, headache, upset stomach, nausea, tachycardia, and feelings of tremulousness, anxiety, or dysphoria. Lethal ingestions of caffeine, although rare, have been reported with most incidents involving intentional overdose in adults 3. Lethal serum levels of caffeine can be as low as 80-100 ug/mL, which can be seen after ingestion of approximately 10 g of caffeine. In massive intentional overdoses, more serious side effects including tachycardia, hypertension, hypotension, tachyarrhythmias, metabolic acidosis, hypokalemia and other electrolyte abnormalities, rhabdomyolysis, seizures often refractory to first-line treatments, and cardiovascular collapse have been seen4. Prior case reports have shown promise with several treatment modalities including AV nodal blocking agents such as esmolol, lipid emulsion therapy, and hemodialysis. Due to the low number of reported cases of caffeine overdoses, the optimal therapy is still unknown. Herein, we report a case of rapid, empiric hemodialysis prior to hemodynamic collapse with a successful outcome.
Case Report Emergency medical services (EMS) were dispatched to the site of a 39 year old male after an intentional caffeine overdose. Upon EMS arrival, the patient’s heart rate was reported to be in the 260-280 bpm, with a narrow complex morphology noted on the monitor. Prehospital orders were given for intravenous (IV) midazolam administration due to combativeness and the patient was then brought to the emergency department. On arrival to the ED, the patient was noted to be agitated, diaphoretic, vomiting, and tachycardic. The patient was able to answer simple questions and admitted to ingesting approximately 50 grams of over-the-counter caffeine tablets approximately one-two hours prior to ED arrival. Telemetry monitoring and frequent electrocardiograms showed that the patient exhibited supraventricular tachycardia (SVT) with frequent premature ventricular contractions and occasional bigeminy. Due to persistent and uncontrolled tachycardia, an esmolol infusion was started at an initial rate of 50 mcg/kg/min and rapid up titration was necessary in order to improve the patient’s hemodynamics. During this time, the patient also required multiple doses of Midazolam for agitation and Trimethobenzamide for nausea and vomiting. Initial workup revealed multiple laboratory abnormalities, including hypokalemia of 2.8 mmol/l, creatinine of 1.55 mg/dL, and a high anion gap metabolic acidosis with lactate of 13.2 mmol/l, bicarbonate of 11 mmol/l, and pH of 7.29 on venous blood gas. A serum caffeine level was also sent to an outside lab for processing. IV potassium repletion and sodium bicarbonate infusion were initiated in hopes of correcting the patient’s multiple metabolic derangements. After consideration of the multiple options for therapy, urgent hemodialysis was elected due to the reported ingestion being well above the known lethal dose. Lipid emulsion therapy was considered but deferred due to the possibility of interfering with the hemodialysis filtration system. Nephrology was contacted from the ED and a temporary dialysis catheter was inserted. The patient was admitted to the intensive care unit and immediately started on a 4 hour hemodialysis session. During this session, the patient’s hemodynamics significantly improved and he was weaned off of the esmolol infusion. Later that evening, the patient’s initial pre-dialysis caffeine level resulted and was found to be well above lethal levels at 254 ug/mL. After the first dialysis session, a repeat caffeine level was drawn and found to be 130 ug/mL (49% decrease from baseline). The following morning another pre-dialysis treatment level was drawn and found to be 86 ug/mL. After a second HD session, the level dropped to 27.4 ug/mL (89% decrease from baseline). The patient received a total of three hemodialysis sessions, with his caffeine level ultimately returning to a normal level two days after admission. The patient’s hospital course was further complicated by mild rhabdomyolysis with CPK levels peaking at 67,600 IU/L, which improved with further IV fluid hydration. Echocardiogram was obtained and showed normal LV function with EF 60-65% and no significant wall motion abnormalities. After 48 hours, the patient was able to be
downgraded to the general medical floors. He was discharged on hospital day eight to an inpatient psychiatric facility.
Discussion Caffeine is consumed by greater than 80 percent of the world’s population, making it one of the most widely used psychostimulants today. An average cup of coffee contains 100-200 mg of caffeine and per the United States Food and Drug Administration (FDA), up to 400 mg daily is unlikely to cause serious harm in a healthy adult. This daily consumption correlates with a normal serum therapeutic range of 8-20 ug/ml. Fatal doses of caffeine have been seen with serum levels as low as 80 ug/ml5. In this case, the patient admitted to ingestion of 50 g of caffeine approximately 1-2 hour prior to ED arrival. Caffeine is largely absorbed in the small intestine, with almost complete bioavailability 45 minutes after ingestion5. Elimination of drug primarily occurs via hepatic metabolism with a half-life estimated to be approximately 4 hours. The degree of protein binding of caffeine is relatively low at 10-35%5. Given the low molecular weight (194.19 g/mol) and the minimal degree of protein binding, caffeine an optimal small molecule to be removed with conventional hemodialysis. Whereas there are numerous case reports of rescue caffeine hemodialysis after cardiovascular collapse or development of acute renal failure, we believe this is one of the first reported cases of intentional caffeine overdose that was preemptively treated with hemodialysis (HD)6–12. Upon evaluation of the extent of this patient’s reported ingestion, clinical presentation, EKG abnormalities, and significantly abnormal vital signs, it was determined that the patient was at significant risk for cardiovascular collapse and death; prompting the decision to initiate early and empiric HD treatment. Following the first HD session, patient’s caffeine level was noted to decrease from an initial level of 254 ug/mL to 130 ug/ml (49% removal). Shortly after initiation of HD, the patient was able to be weaned off esmolol therapy. After the second dialysis session the following day, the patient’s serum level was found to be 27 ug/mL (89% removed). Other proposed treatment modalities of caffeine overdose have included lipid emulsion therapy and antiarrhythmic medications. In one report, the patient had improved mentation after lipid therapy, but subsequently reverted back into ventricular fibrillation later requiring hemodialysis11. Another report showed that a patient with a caffeine ingestion of 40 g was successfully treated with lipid emulsion alone, but this patient had prolonged tachyarrhythmias that did not improve with esmolol. This was likely secondary to esmolol sequestration by lipid emulsion13. Although both hemodialysis and lipid emulsion therapy have shown successful treatment of massive caffeine ingestion, previous studies have not shown one treatment modality to be superior to the other. Our case shows that prompt hemodialysis initiation resulted in rapid improvement of the patients’ tachyarrhythmias and hemodynamic instability, which likely limited long-term sequela of this ingestion. Currently, there is no consensus on initial treatment of caffeine overdose and further study is needed, but our
case provides further evidence that hemodialysis should be considered very early in patients with reported or suspected lethal caffeine ingestion.
References 1.
Fisone G, Borgkvist A, Usiello A. Caffeine as a psychomotor stimulant: mechanism of action. Cellular and Molecular Life Sciences (CMLS). 2004;61(78):857-872. doi:10.1007/s00018-003-3269-3
2.
Ribeiro JA, Sebastião AM, de Mendonça A. Adenosine receptors in the nervous system: pathophysiological implications. Progress in neurobiology. 2002;68(6):377-392. http://www.ncbi.nlm.nih.gov/pubmed/12576292. Accessed August 20, 2019.
3.
Cappelletti S, Piacentino D, Fineschi V, Frati P, Cipolloni L, Aromatario M. Caffeine-Related Deaths: Manner of Deaths and Categories at Risk. Nutrients. 2018;10(5):611. doi:10.3390/nu10050611
4.
Murray A, Traylor J. Caffeine Toxicity.; 2019. http://www.ncbi.nlm.nih.gov/pubmed/30422505. Accessed August 20, 2019.
5.
Willson C. The clinical toxicology of caffeine: A review and case study. Toxicology Reports. 2018;5:1140-1152. doi:10.1016/J.TOXREP.2018.11.002
6.
Ishigaki S, Fukasawa H, Kinoshita-Katahashi N, Yasuda H, Kumagai H, Furuya R. Caffeine Intoxication Successfully Treated by Hemoperfusion and Hemodialysis. Internal Medicine. 2014;53(23):2745-2747. doi:10.2169/internalmedicine.53.2882
7.
Bioh G, Gallagher MM, Prasad U. Survival of a highly toxic dose of caffeine. BMJ case reports. 2013;2013(feb08 1):bcr2012007454-bcr2012007454. doi:10.1136/bcr-2012-007454
8.
Campana C, Griffin PL, Simon EL. Caffeine overdose resulting in severe rhabdomyolysis and acute renal failure. The American Journal of Emergency Medicine. 2014;32(1):111.e3-111.e4. doi:10.1016/j.ajem.2013.08.042
9.
Holstege CP, Hunter Y, Baer AB, Savory J, Bruns DE, Boyd JC. Massive caffeine overdose requiring vasopressin infusion and hemodialysis. Journal of toxicology Clinical toxicology. 2003;41(7):1003-1007. http://www.ncbi.nlm.nih.gov/pubmed/14705850. Accessed August 22, 2019.
10.
Kapur R, Smith MD. Treatment of cardiovascular collapse from caffeine overdose with lidocaine, phenylephrine, and hemodialysis. The American Journal of Emergency Medicine. 2009;27(2):253.e3-253.e6. doi:10.1016/j.ajem.2008.06.028
11.
Schmidt M, Farna H, Kurcova I, et al. Succesfull treatment of supralethal caffeine overdose with a combination of lipid infusion and dialysis. The American Journal of Emergency Medicine. 2015;33(5):738.e5-738.e7. doi:10.1016/j.ajem.2014.11.002
12.
Magdalan J, Zawadzki M, Skowronek R, et al. Nonfatal and fatal intoxications with pure caffeine – report of three different cases. Forensic Science, Medicine and Pathology. 2017;13(3):355-358. doi:10.1007/s12024-017-9885-2
13.
Muraro L, Longo L, Geraldini F, Bortot A, Paoli A, Boscolo A. Intralipid in acute caffeine intoxication: a case report. Journal of Anesthesia. 2016;30(5):895-899. doi:10.1007/s00540-016-2198-x
S0735-6757(19)30630-8 https://doi.org/10.1016/j.ajem.2019.09.018 YAJEM 158528
To appear in:
American Journal of Emergency Medicine
Received Date: Accepted Date:
4 September 2019 24 September 2019
Please cite this article as: B.A. Kohl, K. Kaur, N. Dincher, J. Schumann, T. Carachilo, C. Komurek, Acute intentional caffeine overdose treated preemptively with hemodialysis,, American Journal of Emergency Medicine (2019), doi: https://doi.org/10.1016/j.ajem.2019.09.018
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Inc.
Title: Acute intentional caffeine overdose treated preemptively with hemodialysis Authors: Name 1: Benjamin A. Kohl, MD [corresponding author] Affiliation 1: Division of Critical Care Medicine, Jefferson Northeast Hospital Email 1: [email protected]
Name 2: Kuljit Kaur, DO Affiliation 2: Department of Emergency Medicine, Jefferson Northeast Hospital Email 2: [email protected]
Name 3: Nathan Dincher, DO Affiliation 3: Division of Critical Care Medicine, Jefferson Northeast Hospital Email 3: [email protected]
Name 4: Jessica Schumann, DO Affiliation 4: Department of Emergency Medicine, Jefferson Northeast Hospital Email 4: [email protected]
Name 5: Tara Carachilo, DO Affiliation 5: Department of Emergency Medicine, Jefferson Northeast Hospital Email 5: [email protected]
Name 6: Christopher Komurek, DO Affiliation 6: Department of Emergency Medicine, Jefferson Northeast Hospital Email 6: [email protected]
No external or internal funding was used in the creation of this manuscript. All of the above authors contributed equally in the writing and review of this manuscript.
Abstract Caffeine is the most commonly used central nervous system stimulant. While it has a high LD50 (150-200 mg/kg), when ingested in significant quantity, caffeine can lead to severe and even lethal side effects. Manifestation of toxicity include tachyarrhythmias, seizures, and metabolic derangements which can eventually lead to cardiovascular collapse and death. Studies have shown that lethal doses of caffeine (80-100 ug/mL) can be seen with the ingestion of approximately 10 g of caffeine. Due to the low number of reported cases, there is no consensus on the standard of care for treatment of suspected caffeine overdose. This case details a 39-year-old male who presented to the emergency department (ED) after having ingested 50 g of caffeine. Despite a high dose esmolol infusion, the patient exhibited worsening tachyarrhythmias. Hemodialysis was started empirically given the known amount ingested and ongoing hemodynamic perturbations. Initial pre-dialysis caffeine level was found to be 254 ug/ml. After treatment with two sessions of hemodialysis the patient’s caffeine level decreased dramatically. We believe this is the first case report to demonstrate the success of preemptive hemodialysis, prior to cardiovascular collapse and/or renal failure, in a case of caffeine overdose and should be considered very early in patients presenting with recent toxic ingestion.
Introduction Caffeine (triemethylxanthine, C8H10N4O2) is derived from the purine base, xanthine and is structurally related to adenosine. While there are several target sites of caffeine, the most physiologically important appears to be antagonism at the level of adenosine receptors1. Normally, adenosine mediates downregulation of central nervous system activity through a variety of mechanisms, including the regulation of dopamine. Antagonism of this downregulation results in caffeine’s well-known effects of enhancing cognition and facilitating arousal2. As a reference, a normal cup of coffee typically contains 100-200 mg of caffeine and the Food and Drug Administration considers 400 mg, or 4-5 cups of coffee, per day as a generally safe dose. The effects of caffeine are myriad and the degree to which these effects manifest are largely based on an individual’s sensitivity to methylxanthine. The most commonly reported side effects of caffeine include insomnia, headache, upset stomach, nausea, tachycardia, and feelings of tremulousness, anxiety, or dysphoria. Lethal ingestions of caffeine, although rare, have been reported with most incidents involving intentional overdose in adults 3. Lethal serum levels of caffeine can be as low as 80-100 ug/mL, which can be seen after ingestion of approximately 10 g of caffeine. In massive intentional overdoses, more serious side effects including tachycardia, hypertension, hypotension, tachyarrhythmias, metabolic acidosis, hypokalemia and other electrolyte abnormalities, rhabdomyolysis, seizures often refractory to first-line treatments, and cardiovascular collapse have been seen4. Prior case reports have shown promise with several treatment modalities including AV nodal blocking agents such as esmolol, lipid emulsion therapy, and hemodialysis. Due to the low number of reported cases of caffeine overdoses, the optimal therapy is still unknown. Herein, we report a case of rapid, empiric hemodialysis prior to hemodynamic collapse with a successful outcome.
Case Report Emergency medical services (EMS) were dispatched to the site of a 39 year old male after an intentional caffeine overdose. Upon EMS arrival, the patient’s heart rate was reported to be in the 260-280 bpm, with a narrow complex morphology noted on the monitor. Prehospital orders were given for intravenous (IV) midazolam administration due to combativeness and the patient was then brought to the emergency department. On arrival to the ED, the patient was noted to be agitated, diaphoretic, vomiting, and tachycardic. The patient was able to answer simple questions and admitted to ingesting approximately 50 grams of over-the-counter caffeine tablets approximately one-two hours prior to ED arrival. Telemetry monitoring and frequent electrocardiograms showed that the patient exhibited supraventricular tachycardia (SVT) with frequent premature ventricular contractions and occasional bigeminy. Due to persistent and uncontrolled tachycardia, an esmolol infusion was started at an initial rate of 50 mcg/kg/min and rapid up titration was necessary in order to improve the patient’s hemodynamics. During this time, the patient also required multiple doses of Midazolam for agitation and Trimethobenzamide for nausea and vomiting. Initial workup revealed multiple laboratory abnormalities, including hypokalemia of 2.8 mmol/l, creatinine of 1.55 mg/dL, and a high anion gap metabolic acidosis with lactate of 13.2 mmol/l, bicarbonate of 11 mmol/l, and pH of 7.29 on venous blood gas. A serum caffeine level was also sent to an outside lab for processing. IV potassium repletion and sodium bicarbonate infusion were initiated in hopes of correcting the patient’s multiple metabolic derangements. After consideration of the multiple options for therapy, urgent hemodialysis was elected due to the reported ingestion being well above the known lethal dose. Lipid emulsion therapy was considered but deferred due to the possibility of interfering with the hemodialysis filtration system. Nephrology was contacted from the ED and a temporary dialysis catheter was inserted. The patient was admitted to the intensive care unit and immediately started on a 4 hour hemodialysis session. During this session, the patient’s hemodynamics significantly improved and he was weaned off of the esmolol infusion. Later that evening, the patient’s initial pre-dialysis caffeine level resulted and was found to be well above lethal levels at 254 ug/mL. After the first dialysis session, a repeat caffeine level was drawn and found to be 130 ug/mL (49% decrease from baseline). The following morning another pre-dialysis treatment level was drawn and found to be 86 ug/mL. After a second HD session, the level dropped to 27.4 ug/mL (89% decrease from baseline). The patient received a total of three hemodialysis sessions, with his caffeine level ultimately returning to a normal level two days after admission. The patient’s hospital course was further complicated by mild rhabdomyolysis with CPK levels peaking at 67,600 IU/L, which improved with further IV fluid hydration. Echocardiogram was obtained and showed normal LV function with EF 60-65% and no significant wall motion abnormalities. After 48 hours, the patient was able to be
downgraded to the general medical floors. He was discharged on hospital day eight to an inpatient psychiatric facility.
Discussion Caffeine is consumed by greater than 80 percent of the world’s population, making it one of the most widely used psychostimulants today. An average cup of coffee contains 100-200 mg of caffeine and per the United States Food and Drug Administration (FDA), up to 400 mg daily is unlikely to cause serious harm in a healthy adult. This daily consumption correlates with a normal serum therapeutic range of 8-20 ug/ml. Fatal doses of caffeine have been seen with serum levels as low as 80 ug/ml5. In this case, the patient admitted to ingestion of 50 g of caffeine approximately 1-2 hour prior to ED arrival. Caffeine is largely absorbed in the small intestine, with almost complete bioavailability 45 minutes after ingestion5. Elimination of drug primarily occurs via hepatic metabolism with a half-life estimated to be approximately 4 hours. The degree of protein binding of caffeine is relatively low at 10-35%5. Given the low molecular weight (194.19 g/mol) and the minimal degree of protein binding, caffeine an optimal small molecule to be removed with conventional hemodialysis. Whereas there are numerous case reports of rescue caffeine hemodialysis after cardiovascular collapse or development of acute renal failure, we believe this is one of the first reported cases of intentional caffeine overdose that was preemptively treated with hemodialysis (HD)6–12. Upon evaluation of the extent of this patient’s reported ingestion, clinical presentation, EKG abnormalities, and significantly abnormal vital signs, it was determined that the patient was at significant risk for cardiovascular collapse and death; prompting the decision to initiate early and empiric HD treatment. Following the first HD session, patient’s caffeine level was noted to decrease from an initial level of 254 ug/mL to 130 ug/ml (49% removal). Shortly after initiation of HD, the patient was able to be weaned off esmolol therapy. After the second dialysis session the following day, the patient’s serum level was found to be 27 ug/mL (89% removed). Other proposed treatment modalities of caffeine overdose have included lipid emulsion therapy and antiarrhythmic medications. In one report, the patient had improved mentation after lipid therapy, but subsequently reverted back into ventricular fibrillation later requiring hemodialysis11. Another report showed that a patient with a caffeine ingestion of 40 g was successfully treated with lipid emulsion alone, but this patient had prolonged tachyarrhythmias that did not improve with esmolol. This was likely secondary to esmolol sequestration by lipid emulsion13. Although both hemodialysis and lipid emulsion therapy have shown successful treatment of massive caffeine ingestion, previous studies have not shown one treatment modality to be superior to the other. Our case shows that prompt hemodialysis initiation resulted in rapid improvement of the patients’ tachyarrhythmias and hemodynamic instability, which likely limited long-term sequela of this ingestion. Currently, there is no consensus on initial treatment of caffeine overdose and further study is needed, but our
case provides further evidence that hemodialysis should be considered very early in patients with reported or suspected lethal caffeine ingestion.
References 1.
Fisone G, Borgkvist A, Usiello A. Caffeine as a psychomotor stimulant: mechanism of action. Cellular and Molecular Life Sciences (CMLS). 2004;61(78):857-872. doi:10.1007/s00018-003-3269-3
2.
Ribeiro JA, Sebastião AM, de Mendonça A. Adenosine receptors in the nervous system: pathophysiological implications. Progress in neurobiology. 2002;68(6):377-392. http://www.ncbi.nlm.nih.gov/pubmed/12576292. Accessed August 20, 2019.
3.
Cappelletti S, Piacentino D, Fineschi V, Frati P, Cipolloni L, Aromatario M. Caffeine-Related Deaths: Manner of Deaths and Categories at Risk. Nutrients. 2018;10(5):611. doi:10.3390/nu10050611
4.
Murray A, Traylor J. Caffeine Toxicity.; 2019. http://www.ncbi.nlm.nih.gov/pubmed/30422505. Accessed August 20, 2019.
5.
Willson C. The clinical toxicology of caffeine: A review and case study. Toxicology Reports. 2018;5:1140-1152. doi:10.1016/J.TOXREP.2018.11.002
6.
Ishigaki S, Fukasawa H, Kinoshita-Katahashi N, Yasuda H, Kumagai H, Furuya R. Caffeine Intoxication Successfully Treated by Hemoperfusion and Hemodialysis. Internal Medicine. 2014;53(23):2745-2747. doi:10.2169/internalmedicine.53.2882
7.
Bioh G, Gallagher MM, Prasad U. Survival of a highly toxic dose of caffeine. BMJ case reports. 2013;2013(feb08 1):bcr2012007454-bcr2012007454. doi:10.1136/bcr-2012-007454
8.
Campana C, Griffin PL, Simon EL. Caffeine overdose resulting in severe rhabdomyolysis and acute renal failure. The American Journal of Emergency Medicine. 2014;32(1):111.e3-111.e4. doi:10.1016/j.ajem.2013.08.042
9.
Holstege CP, Hunter Y, Baer AB, Savory J, Bruns DE, Boyd JC. Massive caffeine overdose requiring vasopressin infusion and hemodialysis. Journal of toxicology Clinical toxicology. 2003;41(7):1003-1007. http://www.ncbi.nlm.nih.gov/pubmed/14705850. Accessed August 22, 2019.
10.
Kapur R, Smith MD. Treatment of cardiovascular collapse from caffeine overdose with lidocaine, phenylephrine, and hemodialysis. The American Journal of Emergency Medicine. 2009;27(2):253.e3-253.e6. doi:10.1016/j.ajem.2008.06.028
11.
Schmidt M, Farna H, Kurcova I, et al. Succesfull treatment of supralethal caffeine overdose with a combination of lipid infusion and dialysis. The American Journal of Emergency Medicine. 2015;33(5):738.e5-738.e7. doi:10.1016/j.ajem.2014.11.002
12.
Magdalan J, Zawadzki M, Skowronek R, et al. Nonfatal and fatal intoxications with pure caffeine – report of three different cases. Forensic Science, Medicine and Pathology. 2017;13(3):355-358. doi:10.1007/s12024-017-9885-2
13.
Muraro L, Longo L, Geraldini F, Bortot A, Paoli A, Boscolo A. Intralipid in acute caffeine intoxication: a case report. Journal of Anesthesia. 2016;30(5):895-899. doi:10.1007/s00540-016-2198-x