1 INTRODUCTION

Hypothermia in humans is usually defined as a body core temperature (BCT) of <35.0°C and could be further divided in mild (BCT: 32–35°C), moderate (BCT: 28–32°C) and severe hypothermia (BCT <28°C) (Brown et al., 2012). Symptoms of mild hypothermia may include pallor, cold extremities, shivering, tachypnoea and tachycardia, whereas moderate hypothermia is associated with respiratory depression and impairment of mental function (e.g., paradoxical undressing), bradycardia and cardiac dysrhythmias. In severe hypothermia, patients may suffer from edema, areflexia, oliguria, spontaneous ventricular fibrillation and cardiac arrest (Cheshire, 2016).

A reduced BCT is a common phenomenon in urgent care. In a recent clinical surveillance study, 2.7% of the medical patients in a German emergency unit showed a temperature below of 35.5°C on admission (Scherl et al., 2017)., Hypothermia occurs as a result of an imbalance between heat production and conservation or heat dispersion, often due to a dysfunction of the central thermoregulation (Stine, 1977) controlled via hypothalamic circuits of the preoptic anterior hypothalamic region (Boulant, 2000; Morrison, 2016). Drug-induced postsynaptic dopaminergic stimulation can reduce BCT, whereas serotonergic stimulation can lead to increases in BCT (Docherty & Green, 2010; Green et al., 2005; Saadat et al., 2005).

It has been known for decades that antipsychotic drugs (APD) have the potential to modulate BCT of humans (Ban, 2007). As a symptom of the malignant antipsychotic syndrome, hyperthermia is a familiar idiosyncratic and potentially life-threatening reaction to APD (Ayd, 1956). On the other hand, APD are associated with a decreased BCT (Ban, 2007; Szota & Araszkiewicz, 2019). Chlorpromazine was well-known to reduce BCT since it was introduced in 1952 (Ban, 2007), when it was used in anesthesia to support body cooling during surgery (so-called artificial hibernating) (López-Muñoz et al., 2005). Nowadays, hypothermia has been reported in the context of the use of different, typical as well as atypical, APD (Szota & Araszkiewicz, 2019; van Marum et al., 2007; Zonnenberg et al., 2017) including haloperidol (Signorelli et al., 2013), clozapine (Papazisis et al., 2009), aripiprazole (Kozian et al., 2019), olanzapine (Kreuzer et al., 2012), pipamperone (Kamp, Paschali, & Lange-Asschenfeldt, 2016), risperidone (Brandon Bookstaver & Miller, 2011) and combinations (Kamp, Paschali, Supprian, et al., 2016).

In this context, some APD appear to be more frequently associated with hypothermia. Van Marum et al. (van Marum et al., 2007) reviewed case reports on APD-related hypothermia and analysed cases of hypothermia of the WHO International Database for Adverse Drug Reactions: they discuss risperidone and pipamperone to be high-risk APD with regard to hypothermia. Szota et al. (Szota & Araszkiewicz, 2019) analysed the US Food and Drug Administration database concerning atypical APD-related hypothermia, and found a high prevalence of hypothermia associated with olanzapine, clozapine, and risperidone.

Frequently, hypothermia is caused by environmental factors like cold temperature or insufficient clothing, but could also occur as a result of a medical condition, such as central nervous system or metabolic disorders, infections or effects of medication (Brevik & Farver, 2003). Numerous risk factors for APD-related hypothermia are discussed in previous literature such as advanced age, cerebrovascular dysfunction, sepsis, sedation (e.g. alcohol associated), kidney or liver failure (Szota & Araszkiewicz, 2019; Young, 1996; Zonnenberg et al., 2017). High-risk conditions for hypothermia are conditions with a reduced basal metabolic rate due to for example thyroid, adrenal or pituitary dysfunction (Biem et al., 2003; Paal et al., 2013) or neurological diseases thalamic lesions (White et al., 1996). In a systematic review, Zonnenberg et al. (2017) evaluated 57 cases of APD-related hypothermia. In 88% of the cases, at least one additional risk factor for hypothermia could be detected and 46% of the cases were of advanced age.

Despite the growing number of case reports and analyses of different adverse reaction databases, reliable numbers of incidence of hypothermia or risk factors are yet to be reported. APD-induced hypothermia in psychogeriatric patients has not yet been explored and the actual prevalence of this adverse effect is unknown. Further, a better understanding of risk-factors is necessary. Therefore, we analyzed BCT, medication, age, sex and main diagnoses in a sample of psychogeriatric inpatients (N = 3002) during a period of 4 years in a natural clinical setting. The aim of the present study was (1) to investigate whether medication with APD is associated with an increased incidence of hypothermia in psychogeriatric inpatients, and (2) to evaluate risk factors and high-risk APD. To date, evidence for APD-related hypothermia has been delivered from case reports and databank queries. To our knowledge, this is the first comprehensive study evaluating the incidence of hypothermia in a psychogeriatric inpatient population within a real-life environment.

2 METHODS

Over a period of 4 years (01/01/2015–31/12/2018), data from all inpatients from the three secure psychiatric wards in the Division of Geriatric Psychiatry, Department of Psychiatry and Psychotherapy of the University Hospital of Düsseldorf, Germany, were included in this retrospective analysis. The study was approved by the Ethics committee of the University Hospital of Düsseldorf (study number: 6038R).

2.1 Data acquisition

Patients' electronic medical datafiles were reviewed manually to detect events of hypothermia and classified either as hypothermic patients (HP), if BCT <35°C was measured at least once at any timepoint of treatment, or otherwise as non-hypothermic patients (non-HP). Temperature was measured daily within the clinical routine and in terms of clinical need with a tympanic in-ear device. For all HP, antipsychotic medication as well as the lowest temperature within the course of treatment were extracted from patients' medical records.

For all patients (HP & non-HP), the following data were extracted from electronic files: (1) medication with an APD at any time of their current course of treatment, (2) sex, (3) age (4) and main diagnosis according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) (Dilling et al., 1991). Additionally, the frequency of prescribed APD for the total sample on group-level was included in the analysis. Patients were considered to be exposed to a medication if the respective medication was given at least once during treatment.

2.2 Statistical analysis

The incidence of hypothermia and their 95% confidence interval (CI) for a given subsample of patients was calculated as the number of HP within the subsample, divided by the number of all patients with the same condition. In order to compare the incidence of hypothermia for each subgroup, absolute frequencies were compared on a one-by-one basis using χ2 tests in an explorative manner. As a measure of effect size, the odd ratios (OR) and their 95% CI were calculated. To compare the age of HP and NHP, a two-tailed t-test was conducted (after determining that the data was normally distributed using a Kolmogorov–Smirnov-test). Analysis of selective effects of distinct APDs on the incidence of hypothermia were performed only for substances with five or more prescriptions within the group of HPs using a χ2 test using a Bonferroni correction for multiple testing.

Values are reported as mean ± standard deviation (SD) for continuous variables or as number and percentage for categorical variables, respectively. Statistical analyses were performed using SPSS (IBM SPSS Statistics for Windows, Version 25.0.). Significance was set at p = 0.05 and all p-values were calculated 2-sided.

3 RESULTS

A total of 3002 cases were included in the study. Table 1 illustrates sociodemographic data and psychiatric main diagnoses of our sample of patients.

TABLE 1. Characteristics of the patients Sample of patients Number of cases 3002 Age (years, mean ± SD) 78.0 ± 8.1 Sex (male/female) 1279/1723 Medication with APD 2074 Main diagnosis: Dementia (ICD-10: F00-03) 35.6% Delirium (ICD-10: F05) 16.4% Organic mental disorder (ICD-10: F06) 8.5% Psychotic disorder (ICD-10: F2) 14.1% Affective disorder (ICD-10: F3) 19.8% Any other psychiatric disorder 5.6% Abbreviation: APD, antipsychotic drug.

Sixty-six cases of hypothermia (incidence: 2.2%, 95% CI: 1.7%–2.7%) were detected in the analyzed charts. The mean of temperature lows was 34.6 ± 0.4°C. 32.5°C was the lowest temperature measured in this patient sample.

Medication with APD was associated with an increased incidence (2%, 6%, 95% CI: 1.9%–3.3%) of hypothermia compared to patients not treated with APD (1%,3%, 95% CI: 0.6%–2.0%). [χ2 (1) = 5.1, p = 0.024, OR = 2.0, 95% CI: 1.1–3.8]. Table 2 shows the contingency table of these data.

TABLE 2. Contingency table between the occurrence of hypothermia and treatment with antipsychotic drugs   Treatment with APD Total No Yes Hypothermia No 916 2020 2936 98.7% 97.4% 97.8% Yes 12 54 66 1.3% 2.6% 2.2% Total 928 2074 3002 100.0% 100% 100.0% Chi-square(1) = 5.121; p(2-sided) = 0.024 Abbreviation: APD, antipsychotic drug.

In the sample of HP, pipamperone (N = 39) was most frequently prescribed, followed by risperidone (N = 22) and quetiapine (N = 13). No other APD in this sample fell under the requirements listed in the Statistics section of five or more overall prescriptions. Hence, further analysis was restricted to these three APDs. Figure 1 illustrates the frequency of the prescribed APD for the HP and the total sample.

Frequency of prescription of antipsychotic drugs in the total sample of patients and the subgroup of patients with hypothermia. PIP, pipamperone; RIS, risperidone; QUE, quetiapine; OLA, olanzapine; HAL, haloperidol; Mel, melperone; CLO, clozapine; FLU, flupenthixol; CHL, chlorprothixene

Treatment with pipamperone was highly significantly associated with hypothermia incidence (3.8%, 95% CI: 2.7%–5.0%) compared with any other APD (1.4%, 95% CI: 0.7%–2.1%) [χ2 (1) = 11.9, p = 0.0017, OR = 2.8, 95% CI: 1.5–5.0]. Neither medication with risperidone [χ2 (1) = 0.4, p > 0.5] nor quetiapine [χ2 (1) = 0.7, p > 0.5] was associated with changes in hypothermia incidence compared to patients medicated with any other APD.

In a subsequent analysis, the incidence of hypothermia was compared between the subgroup of patients medicated with any APD other than pipamperone (1.4%, 95% CI: 0.7%–2.1%) compared to those without APD (1.3%, 95% CI: 0.6%–2.0%). Both groups did not differ concerning their incidence of hypothermia [χ2 (1) = 0.1, p > 0.5].

Within the sample of HP, N = 25 patients were treated with a single APD, whereas N = 23 patients received a combination of two APD, and six patients received a combination of three APD. The number of APD did not affect the incidence of hypothermia [χ2 (2) = 2.3, p = 0.311].

Within the sample of HP, N = 18 patients were medicated with a combination of pipamperone and risperidone and six patients were medicated with a combination of pipamperone and quetiapine. No other combination of APD was prescribed five or more times in this sample, hence, further analysis was performed on these two combinations. Within the group of patients treated with pipamperone, neither a combination with risperidone [χ2 (1) = 0.1, p > 0.5] nor quetiapine [χ2 (1) = 0.8, p = 0.378] had an effect on the incidence of hypothermia compared to patients treated with pipamperone alone. Figure 2 illustrates the impact of medication on the incidence of hypothermia.

Incidence of hypothermia associated with antipsychotic drugs (APDs). The prevalence of hypothermia of a given APD was calculated as its number in the hypothermia sample (N[HP]) related to the number of patients exposed to the respective drug in the whole study population (N[total]). Values are shown together with their 95% CIs. * indicates p < 0.05. The dotted line indicates the prevalence of hypothermia within the sample of patients not medicated with an APD (1.3%). PIP, pipamperone; RIS, risperidone; QUE, quetiapine

In APD-treated patients, male sex was associated with an increased incidence of hypothermia (3.5%, 95% CI: 2.2%–4.7%) compared to female (2.0%, 95% CI:1.2–2.8). [χ2 (1) = 4.3, p = 0.038, OR = 1.9, 95% CI: 1.03–3.0].

Within this group, the main diagnosis “delirium” (ICD-10: F 05) showed a clear trend for being associated with an increased incidence of hypothermia (4.1%, 95% CI: 2.0%–6.2%) compared to the other diagnoses (2.3%; 95% CI: 1.6–3.0). [χ2 (1) = 3.6, p = 0.057, OR = 1.8, 95% CI: 0.98–3.3]. Within the group of APD-treated patients, mean age did not differ between HP (N = 54; 78.8 ± 7.9 years) versus non-HP patients (N = 2020; 78.2 ± 8.9 years), t (2072) = −0.6, p > 0.5).

4 DISCUSSION

We found that hypothermia occurred significantly more often in APD-treated patients (2.6%) than non-treated patients (1.3%), with an Odds Ratio of about 2. With a treatment-related incidence of 2.6%, APD-induced hypothermia was a frequent phenomenon at least in geriatric patients, and more common than the current literature is suggesting.

In the present study, medication with APD was found to be associated with a higher incidence of hypothermia but pipamperone was the only APD with a significantly increased incidence of hypothermia. Other antipsychotics (quetiapine and risperidone) were not associated with an increased incidence of hypothermia. After excluding patients medicated with pipamperone from the analysis, there was no further effect of the remaining APD on BCT. Within the current body of literature (Szota & Araszkiewicz, 2019; van Marum et al., 2007; Zonnenberg et al., 2017), quetiapine was not regarded as a high-risk drug concerning APD-induced hypothermia. Also, in animal-studies, the drug did not show an ability to reduce BCT (Oerther & Ahlenius, 2000), so the present results concerning quetiapine are in line with the literature. On the other hand, same evidence strongly indicates risperidone as a potential drug to induce hypothermia. Therefore, the finding that risperidone alone did not increase the incidence of hypothermia in our patient sample was unexpected. An explanation for our finding might be the commonly very low dosages of risperidone in psychogeriatric patients. Typically, risperidone dosage in the elderly does not exceed 1–2 mg/d (Uchida & Mamo, 2009). Most reported cases of risperidone-induced hypothermia refer to patients with higher dosages (up to 6–8 mg/d) (Nagamine, 2016; Perera & Yogaratnam, 2014; Zonnenberg et al., 2019). Hypothermia associated with pipamperone has been reported in numerous previous studies and case reports (Kamp, Paschali, & Lange-Asschenfeldt, 2016; Kamp, Paschali, Supprian, et al., 2016; van Marum et al., 2007; Zonnenberg et al., 2017, 2019). Pipamperone has a quite unique receptor profile. It resembles the most common type of atypical APDs, in that it has a much higher affinity to 5HT2A than D2 receptors. Moreover, in therapeutic dosages in vivo, pipamperone usually reaches a D2 receptor occupancy not exceeding 50% (Schotte et al., 1996). Additionally, its affinity to peripheral α2-adrenergic receptors is quite low (Schotte et al., 1996). As a matter of fact, current literature suggests (Szota & Araszkiewicz, 2019; van Marum et al., 2007; Young, 1996; Zonnenberg et al., 2017) that APD with high 5HT2A-receptor affinity and low D2-receptor affinity are most likely to induce hypothermia. Furthermore, pipamperone has a much lower D2-binding capacity (120 Ki (nM)) compared to risperidone (4.9 Ki (nM)) (Li et al., 2016). Since D2-receptor antagonism has been shown to increase BCT, this difference in D2-receptor binding might be one explanation as to why pipamperone is posing a higher risk for hypothermia than risperidone.

Another hypothesis states that peripheral α2-adrenergic receptors antagonism might contribute to APD-related hypothermia via inhibiting peripheral vasoconstriction in humans (van Marum et al., 2007) as well as in animals (Boschi et al., 1987). However, the present data do not support this hypothesis, because pipamperone does not have a high affinity to peripheral α2 adrenoreceptor.

Although a combination of different APDs is discussed as an additional risk factor in the literature (Kamp, Paschali, Supprian, et al., 2016; van Marum et al., 2007), the present results do not support this hypothesis.

Apart from medication, a few other potential risk-factors for APD-related hypothermia could be discussed. The current literature (van Marum et al., 2007; Zonnenberg et al., 2017) strongly advocates the hypothesis of advanced age as a risk factor for APD-related hypothermia. Thermoregulatory vasoconstriction function in aged skin is impaired in the elderly (Greaney et al., 2016). Hence, elderly patients have difficulties to appropriately decrease skin blood flow to compensate for cooling. Nevertheless, the present study showed no effect of age on hypothermia incidence. We hypothesize that this might be due to a ceiling effect where the impact of age on the risk of hypothermia plateaus at a certain level of neuronal aging, and therefore, older age does not increase the effect. The patients' mean age in the present study was 78.0 years, suggesting that above a postulated threshold of age there might be no additional increase of the hypothermia risk. However, this explanation is quite speculative.

In our patient sample, the main diagnosis “delirium” showed a clear trend toward a significant association with the occurrence of hypothermia. Delirium is an acute brain dysfunction that occurs as the final common pathway of multiple organic disturbances, such as infections, electrolyte disturbances or disturbed acid-base metabolism (Inouye et al., 2014). Infections and electrolyte disturbances are discussed in the current literature (van Marum et al., 2007; Zonnenberg et al., 2017) as potential risk factors for hypothermia. As both hypothermia and delirium have risk factors in common, it seems plausible that both conditions might co-occur. Moreover, delirium is frequent in patients with higher morbidity which also holds true for HP patients.

Male sex was associated with a higher incidence of APD-related hypothermia. Although one review found slightly more case reports regarding male than female sex (Szota & Araszkiewicz, 2019), male sex was not generally regarded as a risk factor to date. There are two different (not mutually exclusive) hypotheses to explain this notion. On the one hand, it is well known, that male compared to female participants differ regarding their perception of thermal comfort. Females are more sensible to a mismatch from optimal temperature, especially concerning cold temperature and show a higher amount of dissatisfaction than males (Karjalainen, 2012). Therefore, it can be speculated, that female patients feel discomfort as an earlier symptom of APD-related hypothermia and therefore are more likely to activate compensatory patterns of behaviour (like adding a layer of warm clothes or using a blanket). These compensatory behaviours might explain the smaller number of hypothermia cases in female patients. On the other hand, when exposed to cold, females—owing a higher amount of vascular reactivity—will more effectively respond with peripheral vasoconstriction (Daanen, 2003), which leads to a reduced acral blood flow and a lower skin temperature compared to males (Burse, 1979). This suggests that females possess an increased ability to conserve heat, which in turn might reduce the risk to develop a hypothermic episode.

4.1 Limitations

This study has some limitations that need to be considered when interpreting these results. First, a retrospective rather than randomized controlled study was conducted, therefore definite causal conclusions can be hardly derived, and the suggestion of risk factors is rather tentative. Second, the current study analysed a specific population, that is, psychogeriatric inpatients from secured wards implicating severe psychiatric conditions, old age, and a high number of somatic comorbidities. It is noteworthy that somatic diseases and advanced age are among the most frequently discussed risk factors for hypothermia (Szota & Araszkiewicz, 2019; Young, 1996; Zonnenberg et al., 2017). Hence, the incidence of APD-related hypothermia in a younger population is probably lower than in the present sample. Third, patients were classified as exposed to an APD if the respective APD was ever given during their actual course of treatment and were regarded as medicated with a combination therapy of APD, if they received two APD at any time, but not necessarily simultaneously. As a result, the number of APD-treated patients might have been overestimated. However, this approach is common in population-based and related studies (Furu et al., 2015).

5 SUMMARY

In summary, given the increased risk of APD-related hypothermia in psychogeriatric patients, physicians should routinely monitor BCT. Early diagnosis of hypothermia and appropriate treatment may prevent fatal outcomes. Since pipamperone has been shown to be a high-risk medication, prescribers should bear this severe adverse drug reaction in mind. Thus, in psychogeriatric patients, the indication for pipamperone should be evaluated on a case-by-case basis.

CONFLICT OF INTERESTS

The authors declare to have no conflict of interest and disclose any possible conflict of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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