Pro Re Nata Medication Use in Acute Care Adolescent Psychiatric Unit

Background

Pro re nata (PRN) medications are commonly used to control aggressive behavior and other signs of emotional disturbance such as agitation, anxiety, and insomnia on psychiatric inpatient units. However, evidence to support the effectiveness of PRN medications is limited (Belgamwar and Fenton 2005; Srivastava 2009; Ahmed et al. 2010; Molloy et al. 2012; Douglas-Hall and Whicher 2015; Khokhar and Rathbone 2016; Zaman et al. 2017; Ostinelli et al. 2018, 2018), and in some cases, they may do more harm than good (Hilton and Whiteford 2008; Gaynes et al. 2016). The data we do have about PRN effectiveness come mostly from studies that compare different PRN medications—rather than examining whether PRN use leads to better outcomes in the first place—or from retrospective reviews of patient outcomes (Gaynes et al. 2016; Zaman et al. 2017). Despite a lack of evidence, the average reported rate of PRN administration on adult inpatient psychiatric units is around 70–80%, ranging from 20% to 100% (Baker et al. 2008). Common PRN medications used on adult units include antipsychotic medications (first and second generation), anxiolytics, and hypnotics, with benzodiazepines being the most frequently used (Martin et al. 2018).

For children and adolescents, data regarding efficacy and indication of PRN medications are even more limited. Some evidence of efficacy comes from studies that did not include a comparison intervention, which limits the conclusions that can be drawn (Hazaray et al. 2004; Khan and Mican 2006; Jangro et al. 2009; Carlson et al. 2010). Of note, the only, double-blind, placebo-controlled study we are aware of, which focused on diphenhydramine for aggressive behavior in children (males, ages 5–13 years old), concluded that diphenhydramine was not superior to placebo in reducing aggressive behavior, although intramuscular (IM) administration of active or placebo was more effective in reducing aggression (Vitiello et al. 1991).

Most data regarding PRN efficacy have been derived from retrospective chart reviews of subjective observational accounts recorded by nurses or physicians (Deshmukh 2010; Asogwa et al. 2017; Baker and Carlson 2018). Existing studies, which vary significantly in terms of diagnostic composition, age, reason for admission, and length of stay, and country, report rates of PRN medication administration ranging from 14% to 80% for reasons, including aggression, agitation, anxiety, or anger (Kaplan and Busner 1997; Bernard and Littlejohn 2000; Dean et al. 2006; Winterfeld et al. 2009; Swart et al. 2011). Kaplan and Busner (1997) reported on prescribing practices in three different inpatient child and adolescent inpatient units in New York area. A high percentage of patients (76–80%) received stat/emergency or PRN medications. The predominant indication for stat or PRN medication was agitation. Antipsychotic medication and diphenhydramine were the most commonly used stat or PRN medications. Bernard and Littlejohn (2000) reported on the use of PRN medication in 500 admissions over a 7-year period in the United Kingdom. Sixty percent of patients received PRN medications, but a small proportion of the patients (11%) accounted for 60% of the total PRN administrations. The most commonly administered PRN was combined oral chlorpromazine and chloral hydrate (84%). Dean et al. (2006), reviewed charts from 122 adolescents with average age of 12.8 years admitted to a short-to-medium stay unit in Australia. More than half of patients were administered at least one PRN sedation medication and the number of doses per patient ranged from 1 to 54 (mean 8, median 3). The most frequently documented reason for PRN administration was agitation (38.7%). Commonly used PRN medications included diazepam, temazepam, chlorpromazine, droperidol IM, haloperidol, olanzapine, and quetiapine. The majority of PRN administration occurred between 2 to 10 pm with a peak at 8 pm. Winterfeld et al. (2009) reported data based on inpatient and partial hospital adolescent population in France. Among 187 patients in this study, only 14% (n = 26) actually received PRN medication, most often for anxiety (67%). Most commonly used PRN medications were hydroxyzine, followed by clonazepam, propericiazine, and loxapine. PRN medications were frequently given during the evening, with a peak at 11 pm. Swart et al. (2011) studied patterns for use of PRN medications among children and adolescents (N = 338) admitted to a residential treatment program in Canada. Approximately 75% of patients were male with a mean age of 12.4 years (standard deviation [SD] = 2.68), 24.9% (n = 84) had a diagnosis of intellectual disability. Half of the patients received at least one PRN. Youth with a significantly longer duration of treatment and youth with mental retardation were more likely to receive PRN medications. The most common reason for PRN administration was a gestural threat of physical aggression (34.7%). Chlorpromazine, lorazepam, and olanzapine were most commonly used.

We are not aware of a similar study reporting on patterns of PRN medications use on inpatient units that serve American adolescents. The most recent descriptive data on this topic were collected three decades ago (Kaplan and Busner 1997). Given differences in the American health care system, relative to Europe, Canada, and Australia (Ridic et al. 2012; Dixit and Sambasivan 2018), as well as differences in treatment practices, it is important to better understand the pattern of PRN administration in the United States. In this investigation, we report on PRN medication use over 6 years for adolescents in an acute care unit. The purpose of this study was to use real-world data to ascertain patterns of use. We hypothesized that adolescents with psychotic disorders would receive more PRN doses than adolescents with nonpsychotic disorders, and that high scores at admission on the Young Mania Rating Scale (YMRS; Young et al. 1978), Hamilton Rating Scale for Depression (; Hamilton 1960), and Brief Psychiatric Rating Scale (BPRS; Overall 1962) would be associated with greater PRN use. In addition, we expected longer length of stay and readmission to be associated with high PRN use. We anticipated that more PRN administration would occur in the evening hours (3 to 11 pm).

Methods

Retrospective chart review was conducted on patients admitted to an acute care inpatient psychiatric unit for adolescents (ages 12–17) between November 1st, 2012 to October 31st, 2018. The unit is a part of free-standing psychiatric hospital adjacent to a medical complex, including tertiary care children's hospital and general hospital. The unit is coeducation with 22 beds. During the day, the unit is staffed with two full-time attending psychiatrists, two full-time staff psychologists, two full-time social workers, two full-time rehabilitation therapists, three dayshift nursing staff, three mental health workers, two full-time teachers, and two full-time teacher's aides. This unit is a teaching unit and has multiple physicians and psychologists in various training stages (psychology extern to psychology fellow and second year postgraduate psychiatric resident to child and adolescent psychiatry fellow). Patients receive individual therapy three times a week and family therapy once a week in conjunction with milieu treatment. The unit applied a token economy system with positive and negative reinforcement until 2016 when dialectical behavioral therapy was incorporated in the milieu. Most of patients also receive psychotropic medications during their stay when deemed necessary by attending psychiatrists. Demographic and clinical data extracted from the electronic medical record (EMR) included age, sex, ethnic/racial background, length of stay, diagnosis on discharge, medications on discharge, scores of clinical rating scales at admission and discharge (YMRS, Hamilton Depression Rating Scale [HAMD] and BPRS), number of PRN (IM and oral) received, and timing of PRN given. PRN medications were categorized into 10 groups; psychiatry, pain, asthma, gastrointestinal, upper respiratory (UR), allergy, endocrine, nicotine, topical skin, and others (See Appendix A1). Verbal consent for PRN medication orders was obtained upon admission from parents or legal guardian of youth. Nonpsychotropic PRN medications were usually requested by patient and/or parents. Psychotropic medications for PRN use were recommended to parents and legal guardians upon admission “just in case” of behavioral dysregulation. Order for IM PRN medications are written upon admission for severe behavioral dysregulation that might cause physical or property damage. IM PRN medication requires activation by physicians to be administered. Diagnoses were made based on clinical interview in accordance with Diagnostic and Statistical Manual for Mental Disorders 5 and IV (depending on whether admission fell before or after the publication of DSM-5; American Psychiatric Association 2001; 2013). Clinical rating scales were completed upon admission and discharge by attending psychiatrists or psychiatric residents; these were completed at the discretion of the treating psychiatrist and, consequently, were not available for all patients. The YMRS was administered to 1405 patients, the HAM-D to 1322 patients, and the BPRS to 164 patients. The protocol was approved by the Health System Institutional Review Board.

Results

Records from 2961 individuals with a total of 3937 admissions were analyzed for the present study. The average patient age was 15.22 (SD = 1.47), 63% were female. The sample was racially diverse, 39% were white and 18% were black. Participants in the high and very high use groups were more likely to be white (X²  = 62.06, p < 0.0001). The average length of stay was 10.5 days (SD = 12.20), group 1 had significantly shorter average stays than the other three groups (F = 24.87, p < 0.0001). The proportion of patients who were hospitalized more than once during the study period was higher in groups 2, 3, and 4 compared to PRN user group 1 (X²  = 49.49, p < 0.0001), and the proportion of patients who required readmission within 30 days of discharge was higher in groups 3 and 4 compared with group 1 (X²  = 20.74, p < 0.0001). The majority of the patients were diagnosed with a mood disorder (depressive disorders 42%, bipolar spectrum disorders 30%), followed by psychotic spectrum disorders (9%) and substance use disorders (6%). Individuals in groups 1 and 2 were more likely to have a depressive disorder (X²  = 125.02, p < 0.0001), whereas those in groups 3 and 4 were more likely to have a bipolar spectrum disorder (X²  = 67.51, p < 0.0001). Youth with developmental disorders were also more likely to be in groups 3 and 4 (X²  = 10.86, p = 0.012). There were no other differences in the diagnostic composition of the use groups. The average YMRS score at admission (n = 1405) was 12.90 (SD = 7.99), average HAM-D (n = 1322) was 21.84 (SD = 11.51), and BPRS (n = 164) was 46.25 (SD = 12.37). YMRS scores varied by group; those in groups 3 and 4 had higher scores than group 1, and the group 4 also had higher scores than groups 2 and 3 (F = 22.54, p < 0.0001) (Table 1).

Sixty-two percent of admissions were administered one or more PRN medications; of those 85% received psychotropic PRN medication (52% of all admissions), and 58% received nonpsychotropic PRN medications (36% of all admissions). Forty-three percent of those who were administered at least one PRN medication got both psychotropic and nonpsychotropic medication (26% of all admissions). The average number of PRN prescriptions was 1.52 (SD = 1.71), and the average number of psychotropic prescriptions was 1.01 (SD = 1.22). As noted above, the average number of PRN doses was 0.90 (SD = 0.90), and the average number of psychotropic PRN doses was 0.35 (SD = 0.60).

Most admissions were in group 1 (69%), followed by group 3 (14%), group 2 (10%), and group 4 (7%). As expected, the most commonly prescribed PRN medications were psychotropic drugs (3992 prescriptions, 67% of all prescriptions), followed by medications for pain (1247 prescriptions, 21%). The greatest discrepancies across use groups in the number of prescriptions were also for psychotropic and pain medications; group 4 got, on average, 2.78 (SD = 1.34) psychotropic drug prescriptions, whereas group 1 got 0.50 (SD = 0.80), this difference was highly significant (F = 953.17, p < 0.0001). Similarly, group 4 got, on average, 0.83 (SD = 0.66) pain prescriptions, whereas group 1 got 0.15 (SD = 0.36), F = 407.91, p < 0.0001. Between-group differences were also observed for eight other classes of medications (there was no difference across groups for endocrine-related medications), although the degree of difference was smaller (Table 2).

The most commonly administered medications were diphenhydramine (32% of all prescriptions), lorazepam (30%), chlorpromazine (14%), melatonin (11%), and haloperidol (6%).

Because the use groups were determined based on the number of PRN doses per day, there were, by definition, differences in total PRN doses per day. In group 1, on average, patients received 0.30 (SD = 15) doses per day, whereas group 4 received 2.86 (SD = 1.10) doses. This pattern extended across almost all classes of medication (the only exception was allergy medication; in this case, group 4 had more doses than group 1, but it was not a statistically significant difference). In most medication classes, group 4 had more doses than groups 2 and 3 too. The largest differences were found in the psychotropic and pain medication classes; group 4 got 1.74 (SD = 1.08) versus the group one's 0.09 (SD = 0.15) psychotropic doses per day, and 0.70 (SD = 1.05) versus 0.03 (SD = 0.09) pain doses Table 2.

Interestingly, although there were large differences in PRN administration, the user groups did not differ significantly in the number of psychotropic medications prescribed at discharge (F = 0.28, p = 0.839).

Clinical characteristics varied as expected across diagnostic groups; length of stay was significantly different across groups (F = 22.61, p < 0.0001) with the longest stays for schizophrenia/psychotic disorders (19.18 days, SD = 19.6) and bipolar spectrum disorders (12.14, SD = 13.1). Patients with schizophrenia/psychotic disorders (10%) or bipolar spectrum disorders (10%) were more likely to be readmitted within 30 days (X²  = 61.98, p < 0.0001) and were more likely to have multiple readmissions during the study period (X²  = 141.42, p < 0.0001); 27% of patients with schizophrenia/psychotic disorders, and 34% of patients with bipolar spectrum disorders. Related, prescription patterns across diagnostic groups showed that bipolar disorder and schizophrenia/psychotic disorder diagnoses were associated with the high PRN psychotropic and total PRN prescriptions. Surprisingly, mood disorder not otherwise specified (NOS) diagnoses received the highest number of prescriptions (both psychotropic, F = 28.48, p < 0.0001 and total, F = 24.47, p < 0.0001). However, this was a small group (five discharge diagnoses) and thus may not be generalizable (Table 3).

Dosing patterns by diagnosis also show higher rates among those with bipolar disorder and schizophrenia/psychotic disorder diagnoses, but the highest number of doses were received by youth with mood NOS, disruptive behavior, or developmental disorders for both psychotropic (F = 19.86, p < 0.0001) and total number of doses (F = 5.37, p < 0.0001). However, as noted above, these groups constituted a very small proportion of overall admissions (Table 3).

More than 50% of doses of all medications were administered between 3 and 11 pm, with the exception of allergy (66% of doses administered 7 am–3 pm), endocrine (63% of doses administered 7 am–3 pm) and migraine medications (47% of doses administered 7 am–3 pm—equivalent to 3–11 pm) (Table 4).

Discussion

Our investigation examined patterns of PRN medication administration on an acute care unit serving adolescents aged 12–17. We anticipated that patients who received higher numbers of PRN medication would have more severe psychopathology, as indicated by high admission scores on the HAMD, YMRS, BPRS, longer length of stay, more frequent readmission, and psychotic disorder diagnoses. The main clinical difference that emerged was that mania symptoms and bipolar diagnoses were associated with higher PRN use. Although bipolar disorder is a severe illness, our expectation was that youth with psychotic disorders (i.e., schizophrenia, schizoaffective, unspecified schizophrenia and related psychotic disorder, brief psychotic disorder, and schizophreniform disorder) would be more likely to need PRN medication due to agitation or not responding to staff redirection (Marzullo 2014; Baker and Carlson 2018). In our patient population, diphenhydramine was the most commonly prescribed psychotropic PRN medication. Diphenhydramine can be prescribed for various reasons, including agitation/anxiety and extrapyramidal symptoms, and also can be used as a sleep aid. Bipolar disorder—and mania—in particular, is associated with significant sleep disturbance (Schwartz and Feeny 2007; Roybal et al. 2011; Van Meter et al. 2016), which may explain why this group was overrepresented in groups three and four. Of note, melatonin was the fourth most commonly used PRN medication in our population.

As expected, patients who were readmitted within 30 days and those who had multiple admissions were also more likely to be in the high and very high PRN use groups. This is logical, as those who need repeated acute care are likely to be more ill. Related, patients with bipolar spectrum disorders had one of the highest rates of 30-day readmission (10%) and were most likely to have multiple admissions over the study period (34%). The unique characteristics of youth with bipolar disorder may make them particularly susceptible to both readmission and high PRN use; bipolar disorder is an episodic disorder and the majority of youth with this diagnosis will experience relapse within 2 years (Birmaher et al. 2009, 2014; Vande Voort et al. 2016). The frequency of relapse can be exacerbated by poor medication adherence, which is a frequent problem among people with bipolar disorder (Sajatovic et al. 2006; DelBello et al. 2007; Baldessarini et al. 2008). Of course, poor treatment adherence is also common among young people with psychotic disorders (Nosé et al. 2003), but an important distinction may be that risk for suicide (i.e., suicidal thoughts and behaviors) are likely to be more prevalent among youth with bipolar disorder than youth with psychotic disorders (Goldstein et al. 2005, 2012; Algorta et al. 2011). In an era where inpatient beds are at a premium (Cummings et al. 2016) and there is a high level of risk that must be met to warrant hospitalization, youth with suicidal thoughts/behaviors are those most likely to be hospitalized (Hayes 2018). This is also reflected in the fact that 45% of the patients in very high use group had discharge diagnoses of bipolar disorder (relative to 11% with psychotic disorders), despite the fact that both disorders have similar prevalence rates in the community (Costello et al. 1996; Australian Government Department of Health 2011; Kelleher et al. 2012; Van Meter et al. 2019).

A novel contribution of this study is the inclusion of all types of PRN medication, not just psychotropic medications. Our rationale for this approach was that nonspecific somatic symptoms could be related to underlying psychiatric issues. The association between depression or anxiety and pain or other somatic complaints are well documented (Henningsen et al. 2003; Campo 2012), but in our sample, youth with depression or anxiety did not have the highest number of nonpsychotropic PRN medication doses. Instead, we found that patients who receive a relatively high number of psychotropic PRN medications were also high nonpsychotropic PRN users. Although not anticipated, this result is intriguing in lieu of a hypothesis; psychiatric symptoms as part of systemic disorder. Multiple studies have shown an association between stress and inflammatory response in the body, as evidenced by increased cytokines, alterations in stress hormone release, and alteration in sympathetic nervous system (Black 2002, 2003). Prolonged provocation of inflammatory processes can result in stress-related disorders such as cardiovascular disease, metabolic abnormalities, neurodegenerative and mental health disorders (Debnath et al. 2011; Friedrich 2014; Uddin and Diwadkar 2014; Kaplan et al. 2015), and youth with mental health disorders are at higher risk for chronic inflammation than their healthy peers (Goldstein et al. 2009; Walker et al. 2014; Du Preez et al. 2016). Consequently, they are also at increased risk of developing chronic physical conditions, including cardiovascular disease, metabolic syndrome, and diabetes, which contribute to a reduction in expected lifespan by 10–15 years (Harris and Barraclough 1998; Miller et al. 2006; Roshanaei-Moghaddam and Katon 2009; Chang et al. 2011; Laursen 2011; Walker et al. 2015; Liu et al. 2017; Simon et al. 2018). Interestingly, youth with bipolar disorder tend to have more medical comorbidity than other mental disorders, which could result in higher use of nonpsychotropic PRN medications (Evans-Lacko et al. 2009; Jerrell et al. 2010; Crump et al. 2013; Kemp et al. 2014). The prevalence of obesity is also higher among youth with bipolar disorder than in other youth (Goldstein et al. 2008, 2016). In our study, patients in groups 3 and 4 were more likely to have bipolar disorder, which may indirectly support the hypothesis that bipolar disorder is indeed a systemic disorder that affects multiple bodily functions (Leboyer et al. 2012).

There are other potential explanations for PRN use. For example, severe psychopathology may decrease distress tolerance, making patients more likely to seek PRN medications for nonserious physical discomfort such as indigestion, sore throat, and cough. However, this hypothesis does not fully explain the results since depressive disorders are often associated with somatic complaints and are not related to increased PRN use for nonpsychotropic medications. Some patients may also seek PRN medication for attention; in addition to the medicine, they receive one-on-one consideration from staff. However, this does not account for the diagnostic disparities we found; there is no reason to assume one group would be more attention-seeking in this way than another. Our finding that youth with high psychotropic PRN use were also likely to be administered more nonpsychotropic PRN medications, which might be influenced by patients being given nonpsychotropic PRN medications to counteract side effects of psychotropic medication. However this hypothesis does not sufficiently explain why medications for UR, skin condition, asthma, and pain are also used more frequently among high and very high PRN use groups.

Consistent with our hypothesis, more than 50% of PRN doses were administered during the evening shift. This finding is aligned with other studies (Dean et al. 2006; Winterfeld et al. 2009), and may indicate that PRN use was primarily as a sleep aid. In addition, on our unit, the evening shift includes family visiting hours, which can contribute to agitation/irritability due to family interaction and generally increases the overall noise level, which can upset some patients.

This study is the only recent investigation of the PRN prescribing patterns on an acute care unit for adolescents in the United States. We found that 62% of patients received at least one PRN prescription (of any type) while admitted and 52% received psychotropic PRN medications. This rate falls within the range of what has been found in other countries—but there is a wide range of PRN use reported. For example, in studies from Australia (Dean et al. 2006) and Canada (Swart et al. 2011), about 75% of hospitalized youth received PRN medication, and in a French study (Winterfeld et al. 2009) only a quarter did. In addition, data from other countries suggest that this number may be falling (Dean et al. 2009). In the United States, as mentioned above, the threshold for hospitalization is high, and the number of available beds has fallen over time (Blanz and Schmidt 2000; Cummings et al. 2016). Most communities are woefully underresourced to meet youth mental health needs (Saxena et al. 2007; Andrilla et al. 2018; Findling and Stepanova 2018). Consequently, the youth served on our acute unit—and others like it—may be more severely ill than those treated in other countries that have nationalized health care and better access to services (Ridic et al. 2012; Dixit and Sambasivan 2018). Related, we thought it possible that there would be differences in PRN prescriptions based on the type of insurance patients had. This was not the case, which is reassuring in that it suggests prescribing patterns that are not influenced by reimbursement.

Conclusion

Psychotropic PRN medications are often used with aim to control acute symptoms, particularly when safety is an issue, as is often the case on acute care units. Still there are questions about the efficacy of psychotropic PRN medications (Srivastava 2009; Baker and Carlson 2018) and there is evidence to suggest that other methods may be more effective for managing some symptoms (Carlson et al. 2019). Given the common use that our results suggest, it is important for future research to closely examine the association between PRN use and a reduction in target symptoms. In addition, considering the relationship we found between nonpsychotropic and psychotropic medication, patients with the most severe psychiatric symptoms may also be experiencing high rates of medical comorbidity, complicating their treatment. For these patients, in need of significant psychiatric and medical care, tailored interventions to precisely address their symptoms should be the goal. Unfortunately, efficacious interventions to manage all patients' symptoms are not available; as such, PRN medication will continue to be a component of acute care despite clear evidence of effectiveness in this population. A concerted effort to quantify the efficacy of PRN use is crucial to best serving youth in acute care settings.

Clinical Significance

Quantifying the pattern of PRN use among adolescents in acute care in the United States underlines importance of examining the efficacy and safety of PRN medications.