Selective serotonin reuptake inhibitor (SSRI) toxicosis in cats: 33 cases (2004–2010)
The authors declare no conflict of interests.
Address correspondence and reprint requests to Dr. Cassandra M. Pugh, The Hope Center for Advanced Veterinary Medicine, 140 Park Street SE, Vienna, VA 22180, USA. Email: firstname.lastname@example.org
To evaluate a population of cats with selective-serotonin reuptake inhibitor (SSRI) toxicosis and characterize the population affected, list products ingested, the clinical signs observed, treatments performed, length of hospitalization, patient outcome, and overall prognosis.
Retrospective study from 2004 to 2010.
Referral veterinary center.
Thirty-three witnessed cat SSRI ingestions.
Measurements and Main Results
The medical records of cats with a witnessed SSRI ingestion identified by review of an animal poison control center electronic database were evaluated. The most common SSRIs ingested were venlafaxine (Effexor; 12/33; 36%), fluoxetine (Prozac; 12/33; 36%), citalopram (Celexa; 6/33; 18%), and escitalopram (Lexapro; 3/33; 9%). Overall, 24% of cats (8/33) became symptomatic, while 76% (25/33) remained asymptomatic. Of the symptomatic cats, sedation was the most common clinical sign (6/8; 75%), followed by gastrointestinal signs (4/8; 50%), central nervous system stimulation (1/8; 13%), cardiovascular signs (1/8; 13%), and hyperthermia (1/8; 13%). Veterinary care was sought in 20 cats (20/33; 61%). Sixteen cats (16/20; 80%) were hospitalized, while 4 cats (4/20; 20%) were treated as outpatients. Treatment for hospitalized patients included administration of IV fluid therapy (14/16; 88%), activated charcoal (12/16; 75%), anti-arrhythmic agents (7/16; 44%), methocarbamol (6/16; 38%), cyproheptadine (6/16; 38%), anti-emetics (5/16; 31%), and sedation (5/16; 31%). Diagnostics included blood work (7/16; 44%), blood pressure measurement (3/16; 19%), and electrocardiogram monitoring (2/16; 13%). Mean hospitalization time for all cases of SSRI ingestion was 14.6 ± 7.8 hours (n = 16). All symptomatic cats in this study (8/8; 100%) had resolution of clinical signs and survived to discharge.
The prognosis for SSRI ingestion in this population of cats was excellent. Decontamination and supportive care for at least 12–24 hours can be considered in cats with SSRI ingestion, particularly venlafaxine to monitor resolution of clinical signs.
central nervous system
selective serotonin reuptake inhibitor
Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter derived from dietary L-tryptophan and converted by tryptophan hydroxylase.
In the central nervous system (CNS), serotonin is produced at the raphe nuclei and released to activate pre- and postsynaptic receptors of the peripheral nervous system. The systemic effects of serotonin include vasoconstriction, platelet aggregation, intestinal peristalsis, and bronchoconstriction.[1, 2] Serotonin also plays a key role in attention, pain perception, aggression, and motor control. Selective serotonin reuptake inhibitors (SSRIs) block the reuptake of serotonin in the presynapse, increasing serotonin molecules at the synaptic cleft and allowing a prolonged pharmacologic effect. In recent years, SSRIs have gained favor over previously used antidepressants in people as they have minimal effects on nonserotonin neurotransmitters, and therefore have less anticholinergic, sedative, and cardiovascular side effects with fewer drug interactions.
In human medicine, SSRIs are predominately used in the treatment of anxiety, depression, and obsessive-compulsive disorders.[1-3] Side effects reported in people include nausea, anorexia, headaches, sexual dysfunction, and insomnia.[1, 5] In human beings, SSRI toxicosis can result in clinical signs of hyperreflexia, myoclonus, seizures, coma, cardiotoxicity (eg, arrhythmias, Q-T prolongation), and in severe cases, death. A specific condition called “serotonin syndrome” (SS) has been identified in people with excessive serotonin concentrations. It is most commonly seen in patients taking multiple concurrent medications, and is characterized by changes in mentation, neuromuscular abnormalities, and autonomic dysfunction.[5-7]
In veterinary medicine, SSRIs are used for behavioral modification, including the treatment of aggression and urine spraying. The most common SSRIs prescribed in dogs and cats are fluoxetine, paroxetine, and sertraline. Other less commonly recommended SSRIs include citalopram, escitalopram, and venlafaxine. The half-lives of fluoxetine, paroxetine, and sertraline in dogs and cats are approximately 26, 20, and 20 hours, respectively, while the half-lives of citalopram, escitalopram, and venlafaxine are unknown in dogs or cats. Therapeutic oral dosages for fluoxetine and paroxetine reported in veterinary medicine typically range from 1–2 mg/kg/d in dogs to 0.5–1 mg/kg/d in cats.[8-10] The use of SSRIs is extra label in cats, and fluoxetine is the only SSRI specifically approved for canine behavior modification.
To the authors’ knowledge, SSRI ingestion and toxicosis in cats have not been well characterized in the veterinary literature. Therefore, the purpose of this study was to evaluate a population of cats with witnessed SSRI ingestion, characterize the patient population, note the SSRI ingested, clinical signs observed, diagnostics performed, length of hospitalization, patient outcome, and overall prognosis. Treatment was also described when the information was available.
Material and Methods
Criteria for selection of cases
The electronic computer database of Pet Poison Helpline,1 an animal poison control center, was retrospectively searched using the search terms “venlafaxine,” “Effexor,”2 “fluoxetine,” “Prozac,”3 “citalopram,” “Celexa,”4 “escitalopram,” “Lexapro,”5 “sertraline,” “Zoloft,”6 “paroxetine,” and “Paxil”7 to identify cats accidentally exposed to SSRIs between 2004 and 2010. Inclusion criteria were defined as those cats witnessed to have ingested an SSRI. Exclusion criteria were nonfeline species, incomplete case records including cases where dosages, clinical signs, or treatments could not be determined, multipet households, nonwitnessed ingestion, or cases where multiple drugs may have been consumed. General organ system categories of clinical signs were used to characterize the data, including CNS depression (eg, sedation, lethargy, mydriasis, ataxia); CNS stimulation (eg, agitation or anxiousness, vocalization, hyperreflexia, tremors, seizures), gastrointestinal signs (eg, vomiting, diarrhea, nausea, drooling), cardiovascular signs (eg, tachycardia, bradycardia, hypertension), and hyperthemia.
Data were collected via a commercially available spreadsheet program8 utilized by a poison control helpline,a along with follow-up questionnaires distributed to the involved owners and veterinarians. Data collected included signalment (including sex, age, breed, and body weight), active ingredient of the SSRI, clinical signs, dose ingested, treatments performed, diagnostic tests, nature of hospitalization (characterized as either inpatient or outpatient care), length of hospitalization when applicable, and outcome. Additional follow-up with pet owners or hospital staff was obtained by phone call when necessary to complete poison control helpline case records. All pet owners or veterinary clinics were contacted at least 3 times for follow-up before the case was considered closed. For patients that did not receive veterinary treatment, follow-up information was obtained via phone conversation with the owner to verify outcome. Cases that were seen by a veterinarian (regardless of inpatient or outpatient care) had follow-up with both the owner and veterinarian to confirm outcome. Patients were considered survivors if they survived to discharge from the hospital, or if confirmation of survival (based on follow-up) was obtained from the pet owner or veterinarian.
Binary logistic regression was used to test whether the development of clinical signs was associated with sex, age, or weight of the patient, or dosage ingested. To test for differences among drugs in mean dosage ingested, a single-factor analysis of variance (ANOVA) was used, followed by Tukey's HSD test (a post hoc multiple comparison test) to identify which drugs were ingested in significantly different quantities. Spearman's rank correlation coefficient was used to test for an association between dosages ingested (mg/kg) and clinical signs. Unlike standard parametric correlations, this analysis detects monotonic relationships between variables regardless of whether these relationships are strictly linear. Fisher's exact test was used to test for an association between the development of clinical signs and the probability of hospitalization. For each analysis, a result was considered significant if P <0.05, using a commercially available computer program.9
Of the 33 cats included in the final analysis, 20 (61%) were male and 13 (39%) were female, with no significant difference between symptomatic and asymptomatic patients (P = 0.52). The mean age was 5.5 ± 5.0 years and there was no significant difference between symptomatic and asymptomatic patients (P = 0.58). The most commonly affected breed was the domestic shorthair, 27/33 (82%), followed by the domestic long hair, 3/33 (9%), Himalayan, 1/33 (3%), Birman, 1/33 (3%), and Siamese, 1/33 (3%). The mean weight was 4.7 ± 2.0 kg; there was no significant difference in mean weight between symptomatic and asymptomatic patients (P = 0.85). There was no significant difference in mean dosage between symptomatic and asymptomatic patients (P = 0.87). The most common SSRIs ingested were venlafaxine (Effexor)b (12/33; 36%) and fluoxetine (Prozac)c (12/33; 36%), followed by citalopram (Celexa)d (6/33; 18%) and escitalopram (Lexapro)e (3/33; 9%). All cats were exposed through accidental ingestion of a medication intended for human use and not by one prescribed for a specific animal.
Only 24% (8/33) cats were symptomatic at the time of the initial phone call to an animal poison control, while 76% (25/33) were initially asymptomatic and remained the same way. Of the 8 cats exhibiting clinical signs, sedation (6/8; 75%) was the most common clinical sign observed in this study. Gastrointestinal signs (eg, vomiting, diarrhea, nausea, drooling) were seen in 50% of cats (4/8), while CNS stimulation (eg, agitation, tremors, seizures), cardiovascular signs (eg, tachycardia, bradycardia, hypertension), and hyperthermia were each observed in 1 patient (1/8; 13%).
In this study, veterinary care was sought in 20/33 (61%) of the cases. Sixteen of 20 cats (80%) were admitted for inpatient hospitalization, while 4 cats (4/20; 20%) were treated on an outpatient basis. The overall mean hospitalization time, including inpatient and outpatient time, was 14.6 ± 7.8 hours (n = 16); no cat was hospitalized for more than 24 hours. Of the 16 cats that were hospitalized, 5 (31%) displayed clinical signs. The presence of clinical signs was not associated with whether the cats were hospitalized or not (P = 0.44). The most common treatment for hospitalized cats was IV fluids (14/16; 88%), followed by activated charcoal (12/16; 75%). Anti-arrhythmic agents such as beta blockers and anticholinergics were administered in 44% (7/16) of cases, along with methocarbamol (6/16; 38%) and cyproheptadine (6/16; 38%). Of the hospitalized cats, 31% received anti-emetics (5/16) and sedatives (5/16; 31%). Only 5/16 cats had emesis induction performed. Blood work (7/16; 44%), blood pressure (3/16; 19%), and electrocardiogram (ECG) monitoring (2/16; 13%) were performed. Complete follow-up information from pet owners and veterinarians was available for 16/33 (48%) cats. All of the hospitalized cats survived to discharge and had complete resolution of clinical signs. No deaths were reported in this study.
Twelve cats (12/33; 36%) ingested venlafaxine. Nine (9/12; 75%) were male and 3 (3/12; 25%) were female. Age ranged from <1 to 12 years. The majority of cats were domestic shorthairs (9/12; 75%) and one each (8%) of domestic longhair, Himalayan, and Birman cats. The mean weight for cats that ingested venlafaxine was 4.6 ± 1.4 kg and the mean dose ingested was 17.4 ± 12.5 mg/kg. Six of the 12 cats (50%) that ingested venlafaxine developed clinical signs, with some cats developing >1 clinical sign. Of the 6 individuals, 5 (5/6; 83%) displayed CNS depression, 3 (3/6; 50%) showed CNS stimulation, 3 (3/6; 50%) displayed gastrointestinal signs, and 1 (1/6; 17%) showed cardiovascular signs (eg, tachycardia with concomittant hypertension). Two (2/6; 33%) cats displayed both CNS depression and CNS stimulation at different times. In 4 cases (4/6; 67%), signs associated with SSRI toxicosis involved >1 organ system. All cats exhibiting gastrointestinal signs after venlafaxine ingestion also exhibited sedation as a clinical sign (3/3). One of the symptomatic cats was being treated with prednisolone at the time of SSRI ingestion (1/6).
Eleven of the 12 (92%) cats that ingested venlafaxine were hospitalized. The single nonhospitalized individual showed signs of sedation but was not treated. This cat ingested the second lowest dosage of venlafaxine (4.6 mg/kg) reported in the study. Two individuals were treated with activated charcoal alone, while the remaining 9 cats received a combination of treatments including IV fluids (9/11; 82%) and activated charcoal (8/11; 73%) as the most common therapies performed.
Twelve cats (12/33; 36%) ingested fluoxetine. Eight were male (8/12; 66%) and 4 (4/12; 33%) were female. Age ranged from <1 to 12 years old. Nine cats (9/12; 75%) were domestic shorthairs, 2 were domestic longhairs (2/12; 17%), and 1 was a Siamese cat (1/12; 8%). Mean weight was 5.0 ± 2.2 kg and the mean dose ingested was 3.5 ± 1.8 mg/kg. Of the cats ingesting fluoxetine, 2 individuals (2/12; 17%) developed clinical signs. The first symptomatic cat, which displayed CNS stimulation (eg, hyperactivity and agitation) and hyperthermia, ingested the largest dosage (6.3 mg/kg). This individual was treated with activated charcoal and released without hospitalization. Incidentally, this symptomatic cat was also being treated with cyproheptadine at the time of SSRI ingestion. The second symptomatic cat (3.7 mg/kg) displayed both CNS depression and gastrointestinal signs, but was not evaluated by a veterinarian and did not receive treatment.
Three cats (3/12; 25%) ingested moderately large doses (4.4–4.7 mg/kg) compared to the mean ingested dose and were hospitalized. Each of these individuals received a combination of treatments that included IV fluids and activated charcoal. None of them developed clinical signs. Emesis induction was performed in 1 cat. Another asymptomatic individual was treated as an outpatient and received an anti-emetic.
Six cats (6/33; 18%) ingested citalopram. Two were male (2/6; 33%) and 4 were female (4/6; 67%). The age ranged from 1 to 16 years, and all affected cats were domestic shorthairs. The mean weight was 4.5 ± 1.7 kg, and the mean dose ingested was 7.3 ± 1.6 mg/kg. Two of the 6 cats were taking methimazole at the time of ingestion. Three (3/6; 50%) cats received veterinary care. Two cats were treated as outpatients (1 was given an anti-emetic and the other was administered activated charcoal). One cat was hospitalized and received a variety of treatments including IV fluids, an anti-emetic, activated charcoal, a sedative, and blood pressure monitoring. None of these treated cats developed clinical signs and were considered asymptomatic.
Three domestic shorthairs ingested escitalopram (3/33; 9%). One cat (1/3; 33%) was male and 2 were female (2/3; 67%). Age ranged from <1 to 9 years. The mean weight was 5.8 ± 4.0 kg and the mean dose ingested was 9.9 ± 6.8 mg/kg. None of the cats developed clinical signs. Only 1 cat, the youngest at 4 months old, received veterinary care. This patient was hospitalized and treated with IV fluids, an anti-emetic, and activated charcoal.
Selective serotonin reuptake inhibitor antidepressant ingestions are frequently seen in feline veterinary medicine patients. In a recent analysis of the top 10 feline toxins, venlafaxine was the most common human medication accidentally ingested by cats in 2011.a In 2008, venlafaxine was among the most widely prescribed SSRI antidepressants in the United States, second only to escitalopram. Due to the growing prevalence of antidepressant use in the United States, veterinarians should be aware of the increasing possibility of feline exposure to SSRI drugs.
Among the 4 drugs noted in the present study, there was no significant association between ingested dose and development of clinical signs. Lack of a relationship between ingested dose and development of clinical signs may be attributed to the accuracy of the pet owner's estimation of the amount of SSRI ingested, a small sample size, and the differences in the pharmacokinetics and pharmacodynamics of the individual SSRI drugs in cats. Likewise, clinical signs may have been limited due to owner public awareness of animal poison control centers, and more rapid decontamination and treatment by the veterinarian.
There are a number of hypotheses to explain why some cats developed clinical signs at very low doses while others remained asymptomatic despite very high ingested doses. Patients that developed clinical signs at low doses may have had underlying metabolic diseases such as kidney disease or hyperthyroidism that could affect drug metabolism; unfortunately in this current study, underlying metabolic disease could not be ruled out since blood work was not performed in most of the cats. Similarly, patients on concurrent medication may have had altered drug metabolism or additive effects. Overall, only 4 cats (4/33) were being treated with other medications at the time of SSRI ingestion. Of the 4 cats, only 2 cats were symptomatic. No conclusion can be made from this small sample size of cats given that each cat had a different combination of SSRIs and concurrent medications.
Several cytochrome isoform enzymes are competitively inhibited by or metabolize SSRIs, and have been identified in human and veterinary medicine, which may contribute to the lack of statistical significance between ingested dose and clinical signs in this study. In dogs and cats, it has been documented that certain drugs can inhibit (eg, ketoconazole, cimetidine) or are metabolized by (eg, tramadol) the cytochrome P450 pathway, thereby enhancing or prolonging SSRI toxicosis by delaying effective metabolism and extending SSRI effects through enterohepatic recirculation.[8, 12] Mechanisms by which SSRI toxicosis can occur include a decrease in serotonin metabolism (eg, MAOIs), a decrease in serotonin reuptake (eg, other SSRIs, tricyclic antidepressants), an increase in serotonin precursors, or an increase in serotonin release. Kalueff et al suggested genetics may contribute to SS-like behavior following administration of serotonergic drugs by genetically altered mice. Further investigations are warranted to evaluate the cytochrome P450 pathway metabolism of SSRIs in veterinary patients and the effects of common concurrent medications.
Selective serotonin reuptake inhibitors are generally highly protein-bound, rapidly metabolized by the liver, and excreted through urine.[2, 3] Venlafaxine, however, is not highly protein-bound and has a shorter half-life in dogs (2–4 h) as compared to the other SSRIs. Newly reclassified as a subtype of antidepressants called serotonin-norepinephrine reuptake inhibitors, venlafaxine is also functionally distinct from the other antidepressants in that inhibition of both serotonin and norepinephrine occurs. Recent evidence in human medicine suggests that there is also reuptake inhibition of dopamine, making venlafaxine less selective for inhibition of serotonin reuptake alone. It is possible that veterinary patients could be at higher risk to develop clinical signs with venlafaxine ingestion due to the combined effects of serotonin, norepinephrine, and dopamine reuptake inhibition. The mean dose of venlafaxine ingested was higher than that of fluoxetine, citalopram, and escitalopram in this study and a larger proportion of cats that ingested venlafaxine became symptomatic compared with the other drugs. Isbister found that venlafaxine at higher dosages in people was more likely to be toxic than at lower doses with a higher fatality rate and an increased risk of seizures and cardiotoxicity. Based on the data collected in this study, however, a higher ingested venlafaxine dose did not increase the incidence of clinical signs, but may prove to be more problematic in cats compared to the other SSRI drugs.
None of the cats in this study that ingested citalopram or escitalopram showed clinical signs. In this study, the lowest toxic doses of venlafaxine and fluoxetine ingested that resulted in clinical signs were 4.6 and 6.3 mg/kg, respectively. However, early decontamination of patients ingesting lower dosages may preclude the establishment of minimum toxic dose for these drugs in cats. While the minimum dose where clinical signs develop in cats could not be documented in any of the 4 SSRI drugs used in this study, the literature does show cats that have been treated with fluoxetine at 50 mg/kg developed gastrointestinal and CNS signs. With chronic administration >1 year of fluoxetine at 3 mg/kg/d, mild gastrointestinal signs have been observed. Tremors, seizures, and bradycardia have also been documented at chronic doses of 5 mg/kg/d. Dogs that have ingested venlafaxine have shown mild depression at doses of 1 mg/kg and tremors noted at 10 mg/kg.2 Unfortunately given the nature of this study, the individual toxic SSRI doses for each drug could not be determined as signs occurred or did not occur over a wide range of doses and successful decontamination may confound the actual absorbed dose.
In this current study, the exact time of onset of clinical signs was not available for 42% of the cats (14/33). For those cats where the time of onset was known (58%; 19/33), clinical signs developed within 1 to 6 hours of SSRI ingestion. All patients that were hospitalized with clinical signs were released within 12–24 hours of admission, suggesting that the clinical signs in cats with SSRI toxicosis resolve within a similar time frame as compared to dogs. Gwaltney-Brant et al evaluated 21 dogs exposed to toxic amounts of 5-hydroxytryptophan (5-HTP), a common over-the-counter herbal supplement converted into 5-hydroxytryptamine (serotonin). Clinical signs developed in 90.5% (19/21) of dogs and the onset of clinical signs occurred between 10 minutes and up to 4 hours postingestion, with the duration of clinical signs lasting up to 36 hours.
The majority of cats in this study (61%) were evaluated at various emergency veterinary hospitals. Regardless of whether or not they displayed clinical signs at the time of presentation, most evaluated cats were hospitalized and received a variety of treatments at that time. Many of these patients received multiple types of treatments and diagnostics. Most cats were asymptomatic at the time of admission and initiation of treatment or specific treatment modalities could not be related with patient outcome. In cats displaying clinical signs of SSRI toxicosis, however, symptomatic and supportive care measures are warranted. Intravenous fluids should be used for supportive measures in dehydrated or clinically symptomatic patients; it is important to note that fluid therapy will not enhance the excretion of these drugs and is not a requirement for therapy in every case. Patients not requiring IV fluids may still benefit by having an IV catheter placed for quick venous access in the event CNS signs (eg, tremors, seizures) develop. Monitoring of blood pressure and heart rate are also warranted in affected patients, as tachyarrhythmias, bradyarrhythmias, hypertension, and hypotension may develop in SSRI toxicosis. The use of anti-arrhythmic medications including beta blockers, such as propranolol, and anticholinergics, such as atropine, can be used when indicated for tachycardia or bradycardia, respectively. It is not clear why some patients with clinical signs were not admitted yet patients that did not display clinical signs were hospitalized. Time of decontamination, owner preferences, and financial limitations may all have been contributing factors determining hospitalization; this information was not available in this study.
At both therapeutic and toxic doses, SS is a common sequela to SSRI toxicosis in human medicine. Serotonin syndrome is a clinical diagnosis and specific criteria have been used to identify this syndrome in human beings (Sternbach's criteria). The criteria are based on the exposure to serotonergic agents in absence of other possible etiologies (eg, infection, substance abuse) with at least 3 symptoms (eg, mentation change, agitation, myoclonus, hyperreflexia, tremors, diarrhea, incoordination, fever) present. In veterinary medicine, signs of SS are not well defined; however, it is still considered a potentially life-threatening drug reaction to excessive serotonin levels. Treatment for SS is typically symptomatic and supportive. The experimental use of cyproheptadine, a serotonin antagonist, has been shown to block SS in animals; however, there are no controlled clinical human or veterinary trials to support its efficacy. No cats in this study were noted to have met the full criteria of SS based on human criteria. In the future, further investigation of SS may be of benefit in veterinary medicine, adapting specific criteria used in human medicine to establish whether SS occurs in veterinary patients and whether using cyproheptadine as a treatment is efficacious.
There were several limitations in this retrospective study. First, historical accuracy of toxicology information provided by the pet owner (eg, the exact number of pills ingested, milligram strength) was based on the pet owner's estimation, which may not always be accurate. As no serum SSRI blood concentrations were measured, definitive exposure could not be confirmed. Nevertheless, to help guide therapy, the most practical information available is typically obtained as part of a thorough history subsequent to initiation of the phone call to an animal poison control center; this information is based on drug availability, milligram size, and verification from an extensive poison database.10 Different time points in which the patient developed clinical signs were not known for all patients, making the exact time of onset and duration of clinical signs difficult to derive. Although the small sample size in this study does not allow for statistical significance in most analyses, the descriptive information obtained is clinically relevant to further increase awareness to owners and veterinarians about the potential for SSRI toxicosis. Increased awareness will likely lead to more reported cases, from which statistically significant information may then be derived.
Overall, the prognosis for SSRI overdose in cats appears to be excellent. Current recommendations for treatment include decontamination (eg, emesis induction, administration of activated charcoal) when appropriate to time of ingestion, heart rate, blood pressure, and ECG monitoring, and hospitalization for supportive and symptomatic care for 12–24 hours for patients with suspected ingestion. Prospective studies evaluating the efficacy of other therapies such as serotonin antagonists are warranted to evaluate benefit to the treatment of patients with SSRI toxicosis.
Pet Poison Helpline, Minneapolis, MN.
Effexor, Pfizer, Mission, KS.
Prozac, Eli Lilly, Indianapolis, IN.
Celexa, Forest Laboratories, St Louis, MO.
Lexapro, Forest Laboratories.
Paxil, GlaxoSmithKline, Middlesex, UK.
Microsoft Excel (2003), Microsoft Corporation, Redmond, WA.
SPSS software for Windows, 17.0.0, SPSS Incorporation, Chicago, IL.
POISINDEX System, Version 5.1, Thomson Reuters (Healthcare), Greenwood Village, CO.