It is often advised that patients who have ingested an overdose of antidepressants (AD) or antipsychotics (AP) are monitored with continuous ECG for minimum of 12–24 hr. These patients are often observed in an ICU. Our aim was to identify the number of patients with AD and/or AP overdose without adverse signs at hospital admission that turned out to need intensive care treatment. The effect of the antidepressants overdose risk assessment (ADORA) system was evaluated in patients with antidepressant as well as antipsychotic overdose. Our hypothesis was that patients with low ADORA do not need intensive care treatment. This retrospective study was conducted in adult patients admitted to the ICU at Odense University Hospital after an overdose with AP and/or AD between 1 January 2009 and 1 September 2014. Patients with predefined adverse signs in the emergency department were excluded due to obvious need of intensive care. Of the 157 patients included, 12 patients (8%) developed events during the ICU stay. Only 3 patients received intubation, vasoactive drugs and/or dialysis. None developed ventricular dysrhythmias. There were no fatalities. All the patients with low‐risk assessment by ADORA within the first 6 hr did not develop events within the first 24 hr after hospital admission. The vast majority of patients with AD and/or AP overdose and no adverse signs at admission did not require intensive care treatment. Low‐risk ADORA identified patients with antidepressant as well as antipsychotic overdose who would not require initial intensive care treatment. This is the first time the ADORA system has been evaluated in patients with antidepressant as well as antipsychotic overdose.

The Danish Poison Information Centre (DPIC) provides over‐the‐phone counselling for the general public and healthcare professionals regarding all acute poisonings. DPIC registers the number of enquiries made and the number of substances included in each case. Antidepressants (AD) and antipsychotics (AP) account for 6.3% and 4.9% calls, respectively. According to DPIC, selective serotonin reuptake inhibitors (SSRI) were the most common AD and chlorprothixene the most common AP 1. Side effects of AD and AP overdose potentially include life‐threatening complications like hypotension, ventricular dysrhythmias or seizures 2-7. Both drugs pose a risk of QRS and QTc interval prolongation, tachycardia and hypotension 2-4, 6. AP more frequently causes QTc interval prolongation than AD, with ventricular fibrillation and torsades de pointes being two possibly fatal complications of QTc interval prolongation 8, 9. AD is shown to more commonly cause seizures than AP 5. The antidepressant overdose risk assessment (ADORA) criteria were first described in 1995 by Garrett E. Foulke 4. The criteria describe the early complications of AD overdose and include QRS interval >0.1 sec., cardiac dysrhythmias, altered mental status (Glasgow Coma Scale <14), seizures, respiratory depression (<8 breaths/min. or assisted ventilation) and hypotension (systolic blood pressure <90 mmHg). The patients were evaluated upon arrival to the emergency department and within the first 6 hr. Depending on their clinical status, the patients were classified into low risk, when not showing any of the ADORA criteria or high risk when 1 or more criteria were present. The study by Foulke showed no subsequent complications among the low‐risk patients. Among the high‐risk patients, 33% had subsequent complications such as pneumonitis, atelectasis, sinusitis, systolic blood pressure <90 mmHg, supraventricular or ventricular dysrhythmias, seizures and respiratory failure 4. Our aim of this retrospective investigation was to identify the proportion of patients with AD and/or AP ingestion with no adverse signs at hospital admission who later developed a need of specific intensive care treatment. Our first hypothesis was that the majority of these patients did not need intensive care treatment. Our second hypothesis was that low‐risk ADORA patients after 6 hr in the emergency department (ED) would not require intensive care treatment. For the first time, the ADORA system was evaluated in patients with antidepressant as well as antipsychotic overdose.

Method This trial was designed as a retrospective study based on all patients admitted to the mixed ICU at Odense University Hospital after AD and/or AP overdose between January 2009 and September 2014. By searching the electronic patient database, all patients who had taken AD and/or AP with age 18 years and above were identified. The following data were recorded: age, gender, weight, height, estimated time of ingestion of AD and/or AP if obtainable, time of hospitalization, name and classification of the drugs, names of co‐ingested drugs including alcohol, clinical findings at the ED (GCS score, seizures, ECG findings, hypotension, respiratory depression), need of endotracheal intubation, charcoal or gastric emptying, whether or not the overdose was accidental or impulsive/suicidal intent, reason for admission to the ICU, complications and treatments in the ICU and length of stay. Patients were excluded in case of obvious need of intensive care (intubation, GCS <9, seizures, hypotension, dialysis). Information from ambulance charts, patients' medical history, urine analysis and blood analysis was collected to identify other drugs ingested. The following definitions were used for classification of clinical findings in the database: hypotension – systolic blood pressure 90 mmHg or less; tachycardia – heart rate above 100 beats per minute; bradycardia – heart rate below 50 beats per minute; QTc interval prolongation – QTc interval above 440 ms; QRS interval prolongation – QRS above 100 ms; arrhythmias – ventricular tachycardia, ventricular fibrillation, atrial fibrillation, atrial flutter or torsades de pointes; time of ingestion – time of arrival to the emergency department, in cases where time of ingestion was not known; and respiratory depression – respiratory rate <8 or the use of naso‐/oropharyngeal tube.

Results Between January 2009 and September 2014, a total of 512 patients diagnosed with poisoning were admitted to the general ICU at Odense University Hospital. A total of 279 patients had not taken AD and/or AP and were thus excluded from the study. Seventy‐six patients were excluded because of obvious need of intensive care: intubation, GCS <9, seizures, hypotension and acute need of dialysis. In total, 157 patients were included in the study (fig. 1). Figure 1 Open in figure viewer PowerPoint Consort diagram of intoxicated patients admitted to the hospital within the study period. Table 1 shows baseline data for the 157 included patients. The median age of the study population was 37 years and 70% were female patients. AP (n = 110) were more frequently ingested than AD (n = 66). The five most common AP and AD ingested are listed in fig. 2. Seventy‐nine patients (50%) ingested other agents in addition to AP and AD. Benzodiazepines and acetaminophen were the two most common drugs co‐ingested by 46% and 32% of the patients, respectively 10. Alcohol was ingested by 50 patients (32%). Table 1. Baseline data for all patients Patients n = 157 Age (years) 37 [26–47] Height (cm) 170 [165–175] Weight (kg) 72.5 [65–84] Female, (%) 110 (70%) Male (%) 47 (30%) GCS score 15 [14–15] Antidepressive substance 661 (38%) SSRI 38 (22%) TCA 8 (5%) Other antidepressive substance 23 (13%) Antipsychotic substance 1101 (63%) Typical antipsychotic 61 (35%) Atypical antipsychotic 56 (32%) Time between overdose and hospital admittance (hours) 2 [1.33–3.75] Time in ED (hours) 1.8 [1.2–2.72] Time in ICU (hours) 12.17 [8.42–17.17] Time in hospital (hours) 16.7 [12.73–24.87] Figure 2 Open in figure viewer PowerPoint The five most common substances used from each group. Antidepressants to the left, antipsychotics to the right. Ninety‐five per cent of the overdoses were classified as suicide attempts or impulsive behaviour (n = 149) and the remainder, 5%, were accidents mostly associated with treatment in psychiatric wards (n = 8). At the time of arrival to the ED, tachycardia was the most frequently noted abnormality 49% (n = 77), with a mean heart rate of 120 beats/min. Other abnormal ECG findings were as follows: QTc interval prolongation (n = 40, 25%), QRS interval prolongation (n = 6, 4%), right bundle branch block (n = 3, 2%) and first‐degree atrioventricular block (n = 1, 0.6%). QTc interval prolongation was known prior to hospital admittance in five of the patients. The most common ingestions involved in QTc prolongation were quetiapine followed by chlorprothixene (fig. 3). Figure 3 Open in figure viewer PowerPoint Patients in the ED with QTc prolongation Red: ingested both AD and AP Blue: Ingested AD or AP Other drugs not accounted for. Referrals from the ED to the ICU were in all 157 cases due to the need of ECG monitoring. In addition, two patients were also at risk of not being able to maintain free airways. Complications during the ICU stay were noted in 12 patients (8%), with some patients having more than one complication (table 2). The most frequent complication observed was hypotension (n = 6) followed by seizures (n = 5), bradycardia (n = 2), respiratory depression (n = 1) and a decreased mental status (GCS from 15 to 8) (n = 1). The most common substance ingested by the patients with complications was chlorprothixene (n = 5), followed by quetiapine (n = 4). Three patients had single substance ingestion with the remaining ingesting more than one substance. Table 2. Summary of 12 patients with complications in the ICU Complication Brief Description Specialized treatment In ICU 1. Hypotension 26/male‐quetiapine IV fluids 2. Hypotension 41/male‐ aripiprazole, citalopram, olanzapine, alcohol Intubation 3. Hypotension 42/female‐ chlorprothixene, levomepromazine, oxazepam, alcohol IV fluids 4. Hypotension 47/male‐chlorprothixene, oxazepam, alcohol. IV fluids 5. Hypotension 74/female‐ amitriptyline, losartan, benzodiazepine in urine, acetaminophen, acetylsalicylic acid Intubation Dialysis Inotropy 6. Hypotension, Bradycardia Seizure 54/female‐nortriptyline, pregabalin, acetylsalicylic acid Intubation Sedation 7. Seizure 23/female‐chlorprothixene, quetiapine, mirtazapine, benzodiazepine in urine, opioid in urine Sedation 8. Seizure 37/female‐ quetiapine, alcohol Sedation 9. Seizure 44/female‐ chlorprothixene Sedation 10. Seizure, Decreased mental status 36/female‐chlorprothixene, quetiapine, oxazepam, acetaminophen, kodimagnyl Sedation 11. Bradycardia 66/female‐ escitalopram IV fluids 12. Respiratory depression 26/female‐ citalopram, olanzapine, oxazepam, tramadol Oxygen Three patients became intubated and received mechanical ventilation. Further, one patient received dialysis and intravenous inotropic medication. The five patients with seizures received benzodiazepine. The patients with hypotension were all except for one corrected with intravenous fluids alone. One patient with low‐risk ADORA within the first 6 hr required intensive care treatment 8 days after hospital admission. Most of the patients (n = 102, 65%) were referred to the psychiatric ward upon discharge from the ICU. The rest were admitted to another ward in the hospital (n = 51, 32%) or directly home (n = 4, 3%).

Discussion Our first hypothesis was that the vast majority of these patients did not need intensive care treatment. However, 12 of 157 patients without adverse signs in the ED developed complications during the ICU stay. As 92.4% of the patients did not develop complications during their stay in the ICU, our hypothesis was confirmed. From a resource utilization perspective, admission to the ICU is not necessary for the majority of patients. The problem is to identify 7.6%, who will develop complications during the ICU stay. Our second hypothesis was that patients with low‐risk ADORA identified 6 hr from ingestion or 6 hr after arrival when time of ingestion was unknown would not require intensive care treatment. For the first time, it has been shown that the ADORA system is able to identify low‐risk patients after antidepressant as well as antipsychotic overdose. All the patients categorized as high‐risk ADORA were among the 12 patients who later developed complications. Two patients were at high risk based on a Glasgow Coma Score <14 due to hypotension and seizures, respectively. Two patients developed seizure or needed intubation. However, one patient from the low‐risk group needed subsequent, specific intensive care treatment: intubation, dialysis and intravenous inotropic medication. That particular 74‐year‐old female patient was intubated 8 days after arrival to the ED. Dialysis was started due to development of acute kidney injury. These complications might have been caused by other factors such as comorbidities and not directly associated with the ingestion of AP/AD. We are, however, not able to exclude with certainty any impact of AP/AD intoxication on later development of complications. Patients with low‐risk ADORA will, however, not develop complications within the first 24 hr after hospital admission. Initial low‐risk ADORA cannot completely exclude the development of later complications. Our second hypothesis was partly confirmed. Patients overdosed with AP and/or AD are in need of continuous ECG monitoring and observation in case they develop cardiac arrhythmias. For historical reasons, observation of the patients is performed in the ICU even though isolated risk of arrhythmia is per se a cardiological condition that could be managed at a lower cost‐effective level such as the emergency room or a cardiological facility. The majority of patients in our study were admitted to the ICU due to risk of cardiac dysrhythmias. Odense University Hospital guidelines state that patients with overdose and respiratory insufficiency, haemodynamic instability and/or risk of cardiac dysrhythmias should be treated in the intensive care unit (ICU) 11. Many psychiatric patients treated with AD or AP drugs have prolonged QTc or QRS interval. Prolonged QTc or QRS interval was therefore only considered a complication if associated with bradycardia. The highest number of cases admitted to the ICU was due to AP overdose. The DPIC report stated that AD exposure was slightly higher than AP 1. In that report, the most common AD was SSRI and the most common AP was chlorprothixene which correlates well with our study. In this investigation, we found that women were more commonly overdosed with AD and/or AP than men and that the most common reason for overdose was suicide or impulsive behaviour. This is in line with similar studies 2, 4, 6. The median age of the patients in our study was 37 years which correlates with Ngo et al., where the median age was 35 years 6. The most common ECG finding observed was simple sinus tachycardia. This is in accordance with other studies 2-4, 6. QTc interval prolongation was a common finding in the ED. AP was more commonly associated with QTc interval prolongation in contrast to the study by Zemrak et al. 8. Of the 157 patients included in the study, 12 patients developed one or more complications in the ICU (table 2). Six patients developed hypotension in the ICU. Of those, five had co‐ingested several non‐AD/AP substances. There was one case of co‐ingestion with an angiotensin‐2‐receptor blocker that is used in the treatment of hypertension and thus can cause hypotension. This is in accordance with a study by Tan et al., showing hypotension as a noted side effect in both substances 3. Chlorprothixene was ingested in two cases of hypotension. Hypotension is both associated with AD and AP but studies that specifically associate chlorprothixene with hypotension have not been found 2, 4, 6. In a study by Reichert et al., AD caused seizures at a higher degree than AP 5. This is in contrast to our study where the majority of patients with seizures in the ICU had ingested AP. Three patients had ingested chlorprothixene and three had ingested quetiapine. Two of these patients had co‐ingested chlorprothixene and quetiapine. These findings correlate with Reichert et al., who showed quetiapine and chlorprothixene causing seizures with a higher frequency than other AP. One patient in the study developed respiratory depression after having ingested, among other drugs, citalopram. In other studies, AD has been shown to be associated with respiratory depression 2, 4. One patient developed a decreased Glasgow Coma Score (GCS 15 to 8) together with seizures. Alteration in mental status such as drowsiness and coma has been associated with quetiapine overdose which was one AP this patient ingested 6. Both patients also ingested oxazepam, a benzodiazepine associated with both respiratory depression and drowsiness. Two patients became bradycardic. One patient ingested solely escitalopram, which has been associated with bradycardia 12.

Limitations Substances ingested were not confirmed by serum levels, but based on information from patient charts retrieved from medical history, urine analysis, along with information from relatives, ambulance technicians and empty drug containers. The ECG findings were predominantly built on information from patient charts due to insufficient ECG scannings.

Conclusion In this retrospective study, only 12 of 157 patients without adverse signs in the ED developed need of intensive care observation and treatment. The majority of these patients were all assessed by ADORA as being at high risk. All the patients with uncomplicated AD and/or AP ingestions with low‐risk ADORA did not develop complications within the first 24 hr. These patients could be observed outside the ICU environment with relevant clinical observation and non‐invasive monitoring including ECG. In case of deterioration, patients should be re‐evaluated. The ADORA system was predictive in patients with antidepressant as well as antipsychotic overdose.