Journal of Toxicology

CLINICAL TOXICOLOGY
Vol. 41, No. 7, pp. 10031007, 2003

CASE REPORT

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Massive Caffeine Overdose Requiring Vasopressin

Infusion and Hemodialysis#
Christopher P. Holstege,1,* Yvonne Hunter,2 Alexander B. Baer,1
John Savory,2 David E. Bruns,2 and James C. Boyd2
1
Division of Medical Toxicology, Department of Emergency Medicine, and
Department of Pathology, University of Virginia, Charlottesville, Virginia, USA

ABSTRACT
Introduction. Massive caffeine overdose is associated with life-threatening hemodynamic
complications that present challenges for clinicians. We describe the highest-reported serum
concentration of caffeine in a patient who survived and discuss the first-reported use of
vasopressin and hemodialysis in a caffeine-poisoned patient. Case Report. A 41-yr-old
woman presented 3 h after ingesting approximately 50 g of caffeine. She subsequently underwent cardiopulmonary resuscitation and received multiple medications in an attempt to raise her
blood pressure and control her heart rate without success. Vasopressin infusion increased her
blood pressure to the point where hemodialysis could be performed. Despite ensuing multisystem organ failure, she survived and has made a complete recovery. Conclusion. Hemodialysis and vasopressin infusions may be of benefit in the management of caffeine-intoxicated
patients who fail to respond to standard therapies.
Key Words: Caffeine; Vasopressin; Hemodialysis; Dysrhythmia; Hypotension.

exposures resolve without significant complications,

adverse events due to caffeine overdose do occur. In
2001 alone, 5562 caffeine exposures were reported to
poison centers in the United States, with half requiring
treatment in a health care facility (1). We describe the
clinical and chemical findings in a patient after a massive

INTRODUCTION
Caffeine is a plant-derived psychoactive stimulant
(1,3,7-trimethylxanthine) widely available in beverages,
herbal products, and both prescription and overthe-counter medications. Although a majority of toxic

#
An abstract of this case was presented to the North American Congress of Clinical Toxicology Meeting held in Montreal, Canada,
October 2001.
*Correspondence: Christopher P. Holstege M.D., Division of Medical Toxicology, Department of Emergency Medicine, University of
Virginia, P.O. Box 800699, Charlottesville, VA 22908-0699, USA; E-mail: ch2xf@virginia.edu.

1003
DOI: 10.1081=CLT-120026526
Copyright # 2003 by Marcel Dekker, Inc.

0731-3810 (Print); 1097-9875 (Online)

www.dekker.com

1004

Holstege et al.

caffeine overdose and the role of vasopressin and hemodialysis in the management.

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CASE HISTORY
A 41-yr-old previously healthy, suicidal female
presented to the emergency department after ingesting
250 200-mg tablets of caffeine (50 g) 3 h previously. On
arrival, she was anxious with a complaint of nausea but
no vomiting. Her initial vital signs revealed temperature
37.4
C,
pulse
206 beats=min,
blood
pressure
140=103 mmHg, respiratory rate 24 breaths=min, and
pulse oximetry reading of 97%. Her pupils were 3 mm
in diameter, equal and reactive to light. Auscultation of
her chest revealed clear breath sounds and tachycardia
without murmurs, rubs, or gallops. Her abdomen was
soft and non-tender with audible bowel sounds. All of
her pulses were palpable. Her skin was warm with a
moist axilla noted. She was oriented only to person and
place but demonstrated a good speech pattern. Testing
of her cranial nerves and motor and light touch sensation showed them to be intact, and no clonus was
elicited.
A wide-complex tachycardia was noted on ECG
(Fig. 1). Twenty minutes after arrival, her blood pressure
dropped precipitously to 90 systolic, and 5 mg of metoprolol were infused in an attempt to slow her heart rate.
Approximately 1 min after administration, the patient

Figure 1.

became bradycardic and sustained a 6-s episode of

asystole. Spontaneous resumption of the wide-complex
tachycardia was followed by another brief bradycardic
and asystolic episode. After once again recovering into
the wide-complex tachycardia, the patients rhythm
degenerated into third degree atrioventricular block
(Fig. 2). At this time the patient had a systolic blood
pressure in the 80s but a preserved level of consciousness. Two grams each of CaCl2 and MgSO4 were infused.
Thirty-five minutes after arrival, she developed a
brief tonicclonic seizure and underwent endotracheal
intubation.
After intubation, the patient developed a wide range
of dysrhythmias including wide-complex tachydysrhythmias, ventricular fibrillation, bradyarrhythmias, asystole
and pulseless electrical activity. The patient had intermittently palpable pulses and cardiopulmonary resuscitation (CPR) was intermittently performed over the
ensuing 5 h. In total, 12 defibrillations were performed
with 8 L of normal saline, 40 meq of potassium, 9 mg
epinephrine, 2 mg atropine, 600 meq of sodium bicarbonate, 150 mg of amiodarone, and 200 mg of lidocaine
infused. She later developed and maintained a wide
complex tachycardia with rate varying between 105
and 152. Despite dopamine (20 mg=kg=min), norepinephrine (20 mg=min), and epinephrine (2 mg=min) infusions, a systolic blood pressure by doppler only in the
50s could be maintained. Vasopressin was begun at
0.2 U=h and advanced to 1.2 U=h in an attempt to
maintain sufficient blood pressure for hemodialysis.

Wide complex tachydysrhythmia at time of arrival.

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Massive Caffeine Overdose

1005

Figure 2.

Third degree atrioventricular block after cardiac arrest.

Approximately 30 min after initiating the vasopressin

infusion, a systolic blood pressure in the 80s was
maintained and hemodialysis was performed 10 h after
arrival to the hospital. During her 5 h of dialysis, her
QRS complex narrowed, her blood pressure steadily
improved, and her epinephrine, norepinephrine, dopamine, and vasopressin infusions were all discontinued.
Initial laboratory values, drawn prior to the patients
seizure and hypotension, were remarkable for a white
blood cell count of 27.2  109=L, hematocrit of 45%,
platelet count of 320  109=L; sodium was 139 mmol=L,
potassium 2.6 mmol=L, chloride 106 mmol=L, bicarbonate 9 mmol=L, urea nitrogen 14 mg=L, creatinine
0.9 mg=L, glucose 324 mg=L, total creatine kinase
103 U=L, and troponin I 2.9 mg=L. Her initial chest
X-ray was unremarkable. Serum caffeine was 405 mg=L
and theophylline was 12.2 mg=L. Ethanol, salicylate, and
acetaminophen were not detectable.
Following dialysis and the cessation of pressor
support, the patient developed no further cardiovascular
instability and remained in sinus rhythm for the rest of
her hospitalization. The patient had a protracted ICU
course. She developed bilateral pneumonia, rhabdomyolysis, and multisystem organ failure. She remained intubated for 17 days following the ingestion. After
extubation, she confirmed the caffeine ingestion and
denied ingesting any other substance. Twenty-four days
after arrival, she was discharged to her home and has
made a full recovery.

DISCUSSION
Clinically, caffeine intoxication is associated with
nausea, vomiting, hypotension, mental status changes,
cardiac dysrhythmias, and seizures. Caffeine induces
these symptoms by affecting a number of different
receptors. Caffeine acts as a non-selective antagonist of
adenosine receptors (2). Adenosine receptors (A) are
divided into several subtypes, with A1 and A2 the best
described. Antagonism of A1 and A2 receptors by
caffeine provokes intractable seizures while at the same
time causing cerebral vasoconstriction in the setting of
increased metabolic activity. A1 stimulation results in
termination of seizure activity (3). During seizures,
adenosine is released from depolarizing neurons as
metabolic activity increases. This adenosine stimulates
A1 receptors at both pre- and post-synaptic neurons to
decrease neurotransmitter release and decrease neuronal
depolarization, respectively. These actions, which are
antagonized by caffeine, block seizure activity before
the neuronal metabolic supply is exhausted. Stimulation
of A2 causes cerebral vasodilatation, ensuring adequate
blood flow to the brain during periods of high metabolic
demand, but this action, too, is blocked by caffeine.
Caffeine can also have profound effects on the cardiovascular system. Reports of caffeine-induced cardiac
dysrhythmias abound in the literature (48). At least four
mechanisms have been proposed for the pro-arrhythmic
potential of caffeine overdoses. First, caffeine increases

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1006

circulating catecholamines (912). Second, caffeine inhibits phosphodiesterase (2,13). Increased circulating catecholamines after caffeine overdose increase b1-receptor
stimulation. Stimulation of b1-receptors increases intracellular cAMP by G protein stimulation of adenylate cyclase.
The activity of cAMP is prolonged because of its decreased
metabolism as phosphodiesterase is inhibited by caffeine.
Subsequently, b1-receptor effects are exaggerated and
tachydysrhythmias are induced. Third, caffeine increases
myocardial intracellular calcium. Caffeine both induces
release of calcium from the sarcoplasmic reticulum and
blocks calciums re-uptake into the sarcoplasmic reticulum
(1316). This resulting increase in cytosolic calcium may
provoke dysrhythmias. Forth, caffeine blocks cardiac A2
receptors that have recently been shown to be antiarrhythmic (17).
The hypotension that has also been noted with
overdoses of caffeine is due primarily to two mechanisms
(18). First, caffeine-induced tachydysrhythmias lead to
inadequate filling of the heart and subsequent decrease in
cardiac output. Second, increased catecholamines stimulate b2-receptors that increase intracellular cAMP. Both
this augmentation of b2-stimulation and phosphodiesterase inhibition lead to a prolonged effect of cAMP
and subsequent vasodilation with resulting hypotension.
There are rare reports of vasopressin infusions being
used in acute human poisonings. There are an increasing
number of reports in the literature describing its use for prehospital cardiac resuscitation, septic shock, hypotension
during cardiopulmonary bypass, and milrinone-induced
hypotension following cardiac surgery (1923). Vasopressin appears to be an especially suitable pressor for refractory hypotension from caffeine because it inhibits both
adenylate cyclase and guanylate cyclase in vascular
smooth muscle. Vasopressin-receptor subtypes are of the
G-protein-coupled receptor superfamily. V1 vascular receptors are located on vascular smooth muscle and mediate
vasoconstriction. This V1-receptor activation mediates
vasoconstriction by receptor-coupled activation of phopholipase C and release of calcium from intracellular stores, via
the phosphoinositide cascade, and extracellular stores, via
calcium channels located on the cell membrane. Vasopressin is a potent vasoconstrictor in skin, skeletal muscle, fat,
pancreas, and thyroid gland. It causes less vasoconstriction
in mesenteric, coronary, and cerebral circulations probably
due to a NO-mediated vasodilating effect of vasopressin on
these circulations (24). In addition, vasopressin potentiates
the contractile effects of catecholamines (25). V2 renal
receptors, which cause the antidiuretic effects of vasopressin, are present in the renal collecting duct system and
endothelial cells. Kidney V2-receptors interact with adenylyl cyclase to increase intracellular cAMP and trigger the
release of more water channels to appear on the cell surface

Holstege et al.

with resultant increased re-absorption of water in the

collecting duct (26). The reported rate of the vasopressin
infusions vary, with most infusions usually begun at 0.03
0.07 units=min and are titrated to effect. This patient
required a dose of 1.2 units=min to sustain her systolic
blood pressure above 80. Potential adverse side effects
of vasopressin include organ ischemia, myocardial
infarction, hypersensitivity reactions, skin necrosis, and
rhabdomyolysis.
Various techniques to enhance elimination of
methylxanthines have been reported in the literature.
Multidose activated charcoal has been advocated in the
treatment of methylxanthine toxicity to both prevent
further absorption of drug and to enhance elimination
by gut dialysis (27). In this case, the patient received a
single dose of activated charcoal but repeat dosing of
charcoal was not performed because of the patients loss
of bowel sounds soon after her initial cardiac arrest.
Hemodialysis has not been previously reported in the
literature for the treatment of caffeine toxicity. The mean
plasma protein binding of caffeine (36%), the molecular
size (194), and the volume of distribution (0.60.8 L=kg)
make hemodialysis a possible modality to enhance elimination. This patient had marked clinical improvement by
the end of 5 h of dialysis, at which time her pressor
support was withdrawn. There have been cases of severe
caffeine toxicity treated with peritoneal dialysis, but this
modality is less efficient at drug clearance than hemodialysis (28,29). The use of charcoal hemoperfusion has
been reported in theophylline poisoning (30). However,
there is no clear indication that charcoal hemoperfussion
would provide increased caffeine clearance over hemodialysis. In addition, charcoal hemoperfusion cartridges
are expensive and not routinely stocked in dialysis units.
Hemodialysis appears to have comparable efficacy in
reducing the morbidity of severe methylxanthine intoxication and is associated with a lower rate of procedural
complications (31). Complications of acute hemodialysis
are rare and include bleeding or thrombosis at the
vascular access sites, thrombocytopenia, lysis of red
blood cells, and introduction of bacteremia.

CONCLUSION
This massive caffeine overdose is remarkable for a
number of reasons. This is the first reported use of either
vasopressin or hemodialysis in caffeine overdose. This is
the highest serum caffeine level reported to have survived. This case also stresses the importance of continued resuscitation despite dire clinical situations in drug
overdose patients.

Massive Caffeine Overdose

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REFERENCES
1. Litovitz TL, Klein-Schwartz W, Rodgers GC,
Cobaugh DJ, Youniss J, Omslaer JC, May ME,
Woolf AD, Benson BE. 2001 Annual report of the
American Association of Poison Control Centers
toxic exposure surveillance system. Am J Emerg
Med 2002; 20(5):391452.
2. Abbott PJ. Caffeine: a toxicological overview. Med J
Aust 1986; 145(10):518521.
3. Eldridge FL, Paydarfar D, Scott SC, Dowell RT. Role
of endogenous adensosine in recurrent generalized
seizures. Exp Neurol 1989; 103(2):179185.
4. Zimmerman PM, Pulliam J, Schwengels J,
MacDonald SE. Caffeine intoxication: a near fatality.
Ann Emerg Med 1985; 14(12):12271229.
5. Price KR, Fligner DJ. Treatment of caffeine toxicity
with esmolol. Ann Emerg Med 1990; 19(1):8587.
6. Chopra A, Morrison L. Resolution of caffeineinduced complex dysrhythmia with procainamide
therapy. J Emerg Med 1995; 13(1):113117.
7. Leson CL, McGuigan MA, Bryson SM. Caffeine
overdose in an adolescent male. J Toxicol Clin
Toxicol 1988; 26(56):407415.
8. Nagesh R, Murphy K. Caffeine poisoning treated by
hemoperfusion. Am J Kid Dis 1988; 12(4):316318.
9. Ishida S, Ito M, Takahashi N, Fujino T, Akimitsu T,
Saikawa T. Caffeine induces ventricular tachyarrhythmias possibly due to triggered activity in rabbits in
vivo. Jpn Circ J 1996; 60(3):157165.
10. Bellet S, Roman L, DeCastro O, Kim KE,
Kershbaum A. Effect of coffee ingestion on catecholamine release. Metabolism 1969; 18(4):288291.
11. Benowitz NL, Osterloh J, Goldschlager N, Kaysen G,
Pond S, Forhan S. Massive catecholamine release from
caffeine poisoning. JAMA 1982; 248(9):10971098.
12. Benowitz, NL. Clinical pharmacology of caffeine.
Annu Rev Med 1990; 41:277288.
13. Myers MG. Caffeine and cardiac arrhythmias. Ann
Intern Med 1991; 114(2):147150.
14. Paspa P, Vassalle M. Mechanism of caffeine-induced
arrhythmias in canine cardiac Purkinje fibers. Am J
Cardiol 1984; 53(2):313319.
15. Boutjdir M, el-Sherif N, Gough WB. Effects of
caffeine and ryanodine on delayed afterdepolarizations and sustained rhythmic activity in 1-day-old
myocardial infarction in the dog. Circulation 1990;
81(4):13931400.
16. Hess P, Wier WG. Excitation-contraction coupling
in cardiac Purkinje fibers: effects of caffeine on
the intracellular [Ca2] transient, membrane
currents, and contraction. J Gen Physiol 1984;
83(3):417433.

1007

17. Schreieck J, Richardt G. Endogenous adenosine

reduces the occurrence of ischemia-induced ventricular fibrillation in rat heart. L Mol Cell Cardiol
1999; 31(1):123134.
18. Pentel P. Toxicity of over-the-counter stimulants.
JAMA 1984; 252(14):18981903.
19. Morris DC, Dereczyk BE, Grzybowski M,
Martin GB, Rivers EP, Wortsman J, Amico JA.
Vasopressin can increase coronary perfusion pressure during human cardiopulmonary resuscitation.
Acad Emerg Med 1997; 4(9):878883.
20. Malay MB, Ashton RC Jr, Landry DW, Townsend RN.
Low-dose vasopressin in the treatment of vasodilatory
septic shock. J Trauma 1999; 47(4):699703.
21. Talbot MP, Tremblay I, Denault AY, Belisle S.
Vasopressin for refractory hypotension during
cardiopulmonary bypass. J Thorac Cardiovasc Surg
2000; 120(2):401402.
22. Baer AB, Holstege CP. Milrinone overdose induced
hypotension reversed by vasopressin and norepinephrine infusions (abstract). J Toxicol Clin Toxicol
2002; 40(5):690.
23. Gold J, Cullinane S, Chen J, Seo S, Oz MC, Oliver JA,
Landry DW. Vasopressin in the treatment of milrinone-induced hypotension in severe heart failure.
Am J Cardiol 2000; 85(4):506508.
24. Aki Y, Tamaki T, Kiyomoto H, He H, Yoshida H,
Iwao H, Abe Y. Nitric oxide may participate in V2
vasopressin-receptor-mediated renal vasodilation.
J Cardiovasc Pharmacol 1994; 23(2):331336.
25. Bartelstone HJ. Vasopressin potentiation of catecholamines in dog, rat, cat, and rat aortic strip. Am J
Physiol 1965; 208:754762.
26. Knepper MA, Nielsen S. Kinetic model of water and
urea permeability regulation by vasopressin in
collecting duct. Am J Physiol 1993; 265:F214F224.
27. Lim DT, Sing P, Nourtsis S, Delacuz R. Absorption
inhibition and enhancement of elimination of sustained release theophylline tablets by oral activated
charcoal. Ann Emerg Med 1986; 15:13031307.
28. Wrenn, KD, Oschner I. Rhabdomyolysis induced by a
caffeine overdose. Ann Emerg Med 1989; 18(1):9497.
29. Walsh I, Wasserman GS, Mestad P, Lanman RC.
Near-fatal caffeine intoxication treated with
peritoneal dialysis. Pediatr Emerg Care 1987;
3(4):244249.
30. Shanon MW. Comparative efficacy of hemodialysis
and hemoperfusion in severe theophylline intoxication. Acad Emerg Med 1997; 4(7):674678.
31. Yamamoto S, Koide M, Matsuo M, Suzuki S,
Ohtaka M, Saika S, Matsuo T. Heparin-induced
thrombocytopenia in hemodialysis patients. Am J
Kidney Dis 1996; 28(1):8285.