Relationship between preoperative antidepressant and antianxiety medications and postoperative hospital length of stay: A retrospective study on abdominal hysterectomy patients

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IN ST IT U T O D E C IÊ N C IA S B IO M ÉD IC A S A B EL S A LA Z A R

M

2020

Relationship between preoperative

antidepressant and antianxiety

medications and postoperative hospital

length of stay: A retrospective study on

abdominal hysterectomy patients

MESTRADO INTEGRADO EM MEDICINA

Pedro do Rego Ponte

Pedro do Rego Ponte: Relationship between preoperative antidepressant

and antianxiety medications and postoperative hospital length of stay:

A retrospective study on abdominal hysterectomy patients

Relationship between preoperative antidepressant

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Relationship between preoperative antidepressant and antianxiety medications and postoperative hospital length of stay: A retrospective study on abdominal hysterectomy patients

Pedro do Rego Ponte

Estudante do 6º ano do Mestrado Integrado em Medicina

Endereço de correio eletrónico: pedroponte12@gmail.com

Mestrado Integrado em Medicina

Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto Centro Hospitalar Universitário do Porto, Hospital de Santo António

Orientador: Sónia Macedo Martins Duarte

Grau Académico: Docente de Mobilidade Externa do Ensino Pré-Graduado do Centro Hospitalar Universitário do Porto

Título Profissional: Assistente Hospitalar de Anestesiologia no Centro Hospitalar Universitário do Porto

Coorientador: Humberto José da Silva Machado

Grau Académico: Professor Catedrático Convidado do Mestrado Integrado em Medicina do Instituto de Ciências Biomédicas Abel Salazar

Título Professional: Assistente Graduado Sénior de Anestesiologia no Centro Hospitalar e Universitário do Porto

Regente das Unidades Curriculares de Terapêutica Geral I & II e Responsável da Unidade Curricular optativa, Anestesiologia e Medicina Peri-Operatória

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Junho de 2020

___________________________________ Assinatura do Estudante

___________________________________ Assinatura do Orientador

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Resumo

Contextualização: O tempo de internamento pós-operatório (LOS) está associado a pior prognóstico no geral, risco aumentado de infeção associada aos cuidados de saúde e iatrogenia. Sendo assim, é importante a identificação dos fatores de risco que condicionam o prolongamento do LOS. O objetivo deste estudo é investigar a possível associação, entre a toma crónica de antidepressivos e ansiolíticos pré-operatória e o LOS, já demonstrado em estudos anteriores, desta vez em pacientes submetidas a histerectomia abdominal total, uma cirurgia comum no nosso centro e uma população

com uso frequente desta medicação.1

Métodos: Estudo retrospetivo que incluiu todas as pacientes submetidas a histerectomia abdominal total no Centro Hospitalar Universitário do Porto (CHUP) entre janeiro de 2018 e março de 2019. A informação das doentes foi colhida através do processo clínico eletrónico. As doentes foram divididas consoante o uso ou não de medicação antidepressiva e/ ou ansiolítica e os LOS comparados.

Resultados: 25% das 260 doentes incluídas no estudo estaria sob terapêutica antidepressiva antes da cirurgia e 25,8% sob terapêutica ansiolítica. Apenas idade, score ASA, e dor máxima pós-operatória foram identificados como fatores de risco de LOS aumentado. Como tal, não foi encontrada correlação significativa entre a toma crónica de antidepressivos ou ansiolíticos e LOS aumentado.

Conclusão: Baseado neste estudo, concluímos que a toma crónica de antidepressivos e ansiolíticos não é fator de risco para LOS prolongado em pacientes submetidas a histerectomia abdominal total. Um estudo prospetivo considerando o bem-estar psicológico dos pacientes e o seu possível impacto no LOS seria proveitoso.

Palavras-Chave

Antidepressivos, Ansiolíticos, Histerectomia, Cuidados Pós-operatórios, Controlo da Dor

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Abstract

Background: Post-operative hospital length of stay (LOS) is associated with worse clinical outcomes, leading to increased risk of healthcare-associated infections and iatrogenesis. Thus, it is important to identify risk factors associated with increased LOS. The goal of this study was to investigate if the chronic use of antidepressant and anxiolytic medication was associated with an increased LOS, as previous studies had already shown, but this time in patients submitted to a total abdominal hysterectomy,

a common surgery in our center, and a population with frequent use of this medication.1

Methods: Retrospective study including all patients subjected to an abdominal hysterectomy at our hospital center between January 2018 and March 2019. Patients’ information was gathered through electronic clinical chart. Patients were categorized by chronic antidepressant and anxiolytic medication usage; a multivariable linear model was constructed to identify LOS predictors and the means were compared. Results: 25% of the 260 patients included in the study were on antidepressant medication prior to the surgery, and 25,8% on anxiolytic medication. Only age, ASA score and maximum post-operative pain score were identified as risk factors for increased LOS. As such, chronic use of antidepressant medication or anxiolytic medication were not related to an increased LOS.

Conclusion: Based on this study, we conclude that chronic antidepressant or anxiolytic medication are not a risk factor for longer LOS on abdominal hysterectomy patients. Further prospective studies need to be conducted to consider the psychological well-being of patients as a possible risk factor.

Keywords

Antidepressant Agents, Anxiolytic Agents, Hysterectomy, Postoperative Care, Pain Management

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Lista de abreviaturas

AN – Ansiolíticos AD – Antidepressivos

ANOVA – Análise de variância

ASA – Sociedade Americana de Anestesiologia BJAN – Revista Brasileira de Anestesiologia BMI – Índice de massa corporal

CES-D – Escala de depressão do Centro de Estudos Epidemiológicos DHD – Dose diária definida por 1000 habitantes por dia

HADS – Escala Hospitalar de Depressão e Ansiedade Hb – Hemoglobina

LA – Anestésico local

LOS – Tempo de internamento hospitalar NRS – Escala de classificação numérica da dor

OECD – Organização para a Cooperação e Desenvolvimento Económico PCA – Analgesia controlada pelo doente

SD – Desvio padrão

SSB – Bloqueio subaracnoideu

SSNRI – Inibidores seletivos da recaptação da serotonina e noradrenalina

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Glossário

ASA score – Escala de classificação de estado físico da Sociedade Americana de Anestesiologia, utilizada para avaliar o risco perioperatório.

CES-D – Breve escala de avaliação do estado depressivo, com 20 questões sobre sintomas auto-reportados pelo paciente na última semana, desenvolvida por Laurie Radolf em 1977.

Conventional post-operative analgesia – A analgesia pós operatória convencional engloba toda a analgesia que possa ser administrada sem intervenção da anestesiologia. São exemplos de não-convencional, a analgesia de caráter epidural, que necessita da introdução de catéter epidural ou a PCA, que obriga à programação da máquina.

Surgical Apgar – O score de Apgar cirúrgico, calculado com base nas perdas hemáticas estimadas, menor pressão arterial média e menor frequência cardíaca no decorrer da cirurgia, é uma escala de 10 pontos em que um baixo valor identifica doentes com maior risco de desfecho desfavorável perioperatório.

Patient Controlled Analgesia – A analgesia controlada pelo doente é a que permite a administração controlada pelo doente de um opióide de modo seguro.

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Índice

Resumo ... i

Abstract... ii

Lista de abreviaturas ... iii

Glossário... iv Artigo... 1 Introdução ... 1 Métodos ... 3 Resultados ... 4 Discussão ... 5 Conflitos de interesse ... 8 Referências ... 9 Lista de Tabelas ... 12 Lista de figuras ... 16

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Esta dissertação/ tese de mestrado tem como base um artigo de investigação submetido à Revista Brasileira de Anestesiologia (BJAN) e como tal, a sua estrutura e formatação seguem as regras de publicação da mesma. O documento relativo às regras de publicação da BJAN pode ser consultado em:

https://www.elsevier.com/wps/find/journaldescription.cws_home/730276?generatepdf=tr ue

O mesmo artigo de investigação foi aceite para apresentação em formato “poster” no Congresso da Sociedade Portuguesa de Anestesiologia de 2020.

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Introduction

Prolonged hospital length of stay (LOS) has been associated with worse prognosis, by greater risk of healthcare associated infection and iatrogenesis. Audits and studies show evidence of 10 years of muscle ageing for some high-risk patients on a LOS greater than 10 days and functional and cognitive decline on older adults (65 and over)

with longer LOS.2_{Hospital acquired infections are also shown as a possible}

consequence of prolonged LOS, increasing mortality rates.3–5_{Hospitals and other}

healthcare facilities would also generally benefit from reducing bed occupancy, improving working and care environment. Identifying risk factors contributing to prolonged LOS could prove beneficial as we try to manage them and diminish their impact. Studies show abdominal hysterectomy patients normally have a 2 to 4 days of LOS on benign pathology and 4 to 11 on malignant pathology, although there are some factors that can negatively influence their LOS, as are uterine weight, estimated blood

loss, surgery duration and post-operative pain management.6–9

The use of antidepressant medication in Portugal has been on the rise and currently ranks fifth on the latest OECD with 104 DHD (defined daily dose per 1000 inhabitants per day), and anxiolytic medication is proportionally the highest in Europe with almost

120 DHD, benzodiazepines being the major contributor.10,11_{On a multicentre}

retrospective study in New York, with non-cardiac surgical patients, there was a 10,5% prevalence of antidepressant use and 10,1% of antianxiety medication use, similar to Portuguese estimated prevalence from the OECD study, and a positive impact on

LOS.1_{On another retrospective study, in Canada, again with elective non-cardiac}

surgical patients, the antidepressant prevalence was 7,8%.12

Besides being prescribed to treat depression, antidepressants can also be used to treat chronic pain. Tricyclic antidepressants like amitriptyline can be prescribed for fibromyalgia and neuropathic pain, and studies have proven the efficacy of SSNRIs like duloxetine in managing diabetic neuropathic pain, fibromyalgia, and chronic

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With these assumptions in mind, our goal was to determine the relationship between antidepressant and anxiolytic medication and hospital length of stay in patients submitted to abdominal hysterectomy, trying to find specific medication with greater risk and a possible relation with post-operative pain scores.

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Methods

This retrospective investigational study included every consecutive patient submitted to abdominal hysterectomy from January 2018 to March 2019. The study was approved by the Hospital Board and Ethics Committee with the approval number 2019-208(167-DEFI/174-CE).

We based the size of our sample on previous studies with similar focus and considered

10 patients per collected variable, expecting a possible 25% loss of data.19_{Patient data}

was collected from the electronic clinical chart database. Demographic, clinical, surgical procedure, anaesthesia, recovery, and post-operative care information data was collected, which included, age, BMI, medical comorbidities, pre-operative haemoglobin, smoking, alcohol and drug habits, pathology nature (benign/ malignant), surgery duration, uterine weight, surgical Apgar (estimated blood loss, mean blood

pressure, minimum cardiac rate), surgical complications and ASA score.8,19_Patients

were separated in two main groups, those who were on antidepressant or anxiolytic medication and those who were not, and their LOS was compared, as well as the maximum recorded post-operative pain score on the numeric rating scale (0-10). On a first approach, The Student t-test for independent samples was used to compare the mean LOS between both groups. The same test was also applied considering the use of antidepressants and anxiolytic medication separately. A multivariable linear model to predict the LOS was constructed using, age, BMI, pre-op Hb, smoking habits, alcohol consumption, uterine pathology, uterine weight, estimated blood loss, minimum mean blood pressure, minimum heart rate, surgical Apgar, complications and major complications, 30 day readmission, ASA score, anaesthesia type, post-operative analgesia, maximum post-operative pain, antidepressant and anxiolytic medication as predictive factors. Minor and major complication criteria were based on previous studies, where minor complications included: haemorrhage not requiring transfusion, infection, or fever ≥38ºC, haematoma not requiring drainage, deep vein thrombosis, cervical stump problems, and minor anaesthesia problems. Major complications were

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Results

There were 260 patients that underwent total abdominal hysterectomy and were included in this study (none excluded). The demographic information is shown on Table I. Data relative to the surgical procedure and anaesthesia on Table II. The median length of stay was 4 days (minimum 2, maximum 38). During post-operative care, the median pain score was 4 (minimum 0, maximum 10) with the most common post-operative analgesia technique being conventional analgesia. There were 23 surgical complications (8,8%), of those, 7 were major (2,7%). Major complications included intraoperative blood transfusion, bladder laceration and hemoperitoneum. The readmission rate at 30 days was 5,4% (14 patients).

Mean LOS was not significantly different between antidepressant (AD) or anxiolytic (AN) group with a mean LOS of 5,25 days (SD=0,291 days), and the control group with a mean LOS of 4,60 days (SD=0,262 days, p=0,101, t-test for independent samples), results are shown on Figure 1. Independently considering AD and AN medication yielded similar results. Patients taking antidepressants had a mean LOS of 5,25 days (SD=0,335 days) and patients not taking antidepressants, 4,72 days (SD=0,237 days, p=0,250). Patients taking anxiolytics had a mean LOS of 5,44 days (SD=0,408 days) and those not taking any antianxiety medication had 4,65 days (SD=0,408, p=0,090), shown on Figure 2.

The multivariable linear model to predict LOS had a 31,5% accuracy (R2=0,315). Identified risk factors for increased LOS are shown on Table 3 along with respective respective importances. Pain scores from the NRS and their respective LOS means are represented on Table 4. The analysis of variance is significant (ANOVA p<0,001), suggesting LOS means vary between pain scores, but no specific value or values can be identified as responsible for this difference. Spearman correlation is positive R=0,22 (p<0,001), suggesting LOS increases with Post-operative pain score. Through the non-parametric Mann-Whitney test, we found significant differences betweem the LOS means on groups with surgical complications (p<0,001) and major complications

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Discussion

From the 2019 OECD report, the 104 DHD antidepressant and 120 DHD anxiolytic value provide a rough estimate of 10,4% of the Portuguese population on antidepressants, as well as 12,0% on anxiolytics. This estimate is in line with the prevalence reported by studies on other developed nations, like the New York based Vashishta et al. (2018) and the Canadian based Sutherland et al. (2013), mentioned

above.1,12_{Despite having reported a much higher prevalence with 25,0 % AD use and}

26,2% AN use, our study focused on hysterectomy patients, an all-female population with and age range starting at 32 years. A 2016 study on the northern Portugal population showed a 15,1 % prevalence of AD use, which is 5% higher than our

estimate for the general population, and females as the main consumers (77,6%).21

Also, the Lewer et al. (2015) study which included 27 European countries, showed a 15,7% AD use prevalence in Portugal (the highest of the 27 countries) and an increased antidepressant use on women and people aged 40-54, supporting this

difference.22

Our mean LOS was 4,85 days, which stands in between the expected LOS for abdomen hysterectomy patients with benign and malignant pathology 2 to 4 days and 4 to 11 days, respectively. Malignant pathology accounted for 16,9% of accounted procedures, possibly increasing the LOS mean beyond what would be expected from benign pathology.

The mean LOS on the groups on AD or AN medication and on the groups independently tested for AD and AN show an increase on the mean LOS, also shown on Figure 2, although with no statistical significance. Some studies, like the Sutherland

et al. (2013) show similar results, although the two groups were not similar.12_Other

studies find positive correlation between chronic use of antidepressant medication and

anxiolytic medication and LOS like the Vashishta et al. (2018).1,23,24_The

aforementioned study was a retrospective multicentre study including all non-cardiac surgery specialities with a large sample, although the authors consider the possibility

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Jordan, focused on cardiac surgery patients and used the Arabic equivalent of the Hospital Anxiety and Depression Scale (HADS), a scale designed for evaluating emotional distress on non-psychiatric patients and criticized for inconsistent results

regarding the concepts of anxiety and depression.26,27

On this study, estimated blood loss, ASA score, age, complications, major complications, and maximum post-operative pain were shown to be significant predictors of LOS with crescent order of importance. Estimated blood loss had a low correlation with LOS possibly due to a low amplitude of values, as 75% of the patients had losses of 150 ml and below. BMI, malignant disease, surgery duration and surgical Apgar score did not correlate with LOS on our statistical model.

BMI is linked to several comorbidities including Diabetes Mellitus, Hypertension and breathing problems that could complicate surgery and post-operative care, just as malignant pathology could require a more radical surgical approach and aggressive procedures. Despite not correlating with LOS, BMI values were consistent with expected for the Portuguese population with more than 50% of our patients being overweight (BMI>25). Only 44 of 260 (16,9%) patients included in the study suffered from malignant disease, which could account for not correlating with LOS. Also, surgery duration values were relatively low with 75% of surgeries shorter than 100 minutes. The surgical Apgar score is calculated with estimated blood loss, lowest mean arterial pressure, and lowest heart rate measured during surgery. Although estimated blood loss had positive correlation and significance, neither surgical Apgar score nor its other variables were related to LOS. Uterine weight had been shown as a LOS predictor on the Lonky et al. (2017) although with a much larger sample and excluding

malignant pathology.6

Limitations in our study include the size of the sample, possible reason for not establishing correlation between some expected risk factors. The same factor rendered us unable to test specific medication classes as was one of the initial goals. As a retrospective study it would not have been possible, with use of electronic clinical

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This way, we propose a follow-up prospective study to differentiate between the physiological impact of antidepressant medication and anxiolytic medication and the underlying psychiatric conditions. This could be achieved with mental health questionnaires like the PHQ-2, the HADS or the CES-D or with clinical psychiatric evaluation on the pre-operative period. If indeed, pre-operative well-being and mental state could have an impact on LOS, we suggest considering it a priority on perioperative patient assessment and care as well as post-operative pain management, which was identified as a LOS predictor on this study. Minimum post-operative pain should be obtained, while pondering the cost-benefit relation of higher analgesic doses. Patient comorbidities should be optimized as much as possible in the pre-operative period, as ASA score was found to correlate with LOS in this study. Pre-operative conditioning could be a strong ally on higher ASA scores on reducing the consequences of surgical trauma and their systemic effects. Physical and nutritional conditioning on the pre-operative period have shown significant improvements on

mental and physical stress on the post-operative period.28,29

Although there are known surgical adverse effects caused by some antidepressants, including tricyclic and SSRI, like increased bleeding risk and arrhythmia, guidelines do

not recommend their suspension on basis of potential withdraw syndrome.18,30_Proving

no relationship between their chronic use and LOS could support this recommendation. Studying and identifying the risk factors responsible for prolonged hospital length of stay in surgical patients could prove useful. Managing these risk factors could result in a lower probability of infection and less iatrogenesis. As well as a reduction of the cost, either to the patient or for the healthcare provider, and the dissatisfaction that naturally comes with it.

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Conflicts of interest

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Table I - Demographic data

Quantitative

Variables N Mean

Standard

Deviation Minimum Maximum

Age (years) 260 52.8 11.4 32 94

Weight (kg) 258 70.48 14.71 42 138

BMI (kg/m2₎ ₂₅₇ _27.54 _5.42 _17.65 _49.48

Pre-op Hb

(g/dL) 251 12.78 1.72 5.60 15.80

Categoric Variables Frequency Percentage

Smokers 41 15,8 Alcohol 9 3,5 Uterine Pathology Benign 212 81,5 Malignant 44 16,9 Borderline 4 1,5 ASA score 1 40 15,4 2 177 68,1 3 43 16,5 Antidepressants 65 25,0 Anxiolytic 68 26,2 Both medications 101 38,8

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Table II – Surgery and anaesthesia data Quantitative Variables N Mean/ (Median) Standard

Deviation Minimum Maximum

LOS (days) 260 4.8 3.2 2 38

Surgery duration

(min) 260 86.0 30.6 38 192

Est. Blood loss (mL) 260 119.13 84.496 20 900

Minimum mean blood

pressure (mmHg) 260 69.6 12.6 40 115

Minimum heart rate

(bpm) 260 60.7 38.5 37 660

Surgical APGAR 260 (8.0) n.a. 4 10

Categoric Variables Frequency Percentage

Uterine Weight 0-250g 163 62,7 250-500g 51 19,6 >500g 33 12,7 Complications 23 8,8 Major Complications 7 2,7 30 day readmission 14 5,4 Anaesthesia type Balanced general 93 35,8 Combined 117 45,0 Intravenous 12 4,6 Locoregional 11 4,2 Post-op analgesia Conventional 89 34,2 Epidural + LA 10 3,8 Epidural - morphine 77 29,6 PCA – morphine 27 10,4 PCA – sufentanil 13 5,0 Epidural – sufentanil 2 0,9 SSB – morphine 1 0,5 0 1 0,4 1 10 3,9

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Table III – Predictors yielded by Multivariable Linear Model predicting LOS and

respective importance.

Variables Importance

Est Blood Loss 0,0249

ASA Score 0,0277

Age 0,0611

Complication 0,1089

Major Complication 0,2351

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Table IV – Hospital Length of stay (LOS) predictors identified by the multivariable linear

model and their impact on LOS.

LOS (days)

Max post-operative

pain score N Mean Standard Deviation Minimum Maximum

ANOVA p<0.001 0 1 2,00 . 2 2 R=0.22 p<0.001 1 10 4,00 0,00 4 4 2 123 4,28 1,09 3 11 3 81 5,43 3,80 3 22 4 22 5,09 1,95 4 12 5 12 5,00 1,65 3 9 6 2 4,00 0,00 4 4 7 1 5,00 . 5 5 8 3 15,33 19,63 4 38 10 1 4,00 . 4 4 Total 256 4,86 3,19 2 38

ASA score ANOVA

p=0.0018 1 40 4,87 5,39 3 38 n.a 2 177 4,55 1,89 3 20 p=0.013 3 43 6,07 4,24 2 22 Total 260 4,85 3,167 2 38 Complications Y 23 8,43 3,17 2 38 p<0.001 N 237 4,51 1,90 3 20 Major complications Y 253 4,65 2,24 3 22 p=0.001 N 7 12,14 12,56 2 38

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Figure 1 – Hospital Length of stay (LOS) distribution considering the patients in the group

taking AD or AN versus the patients in the control group (not taking AD or AN). T-test p=0,101.

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Figure 2 – Hospital Length of stay (LOS) distribution considering the patients in the

group taking AN versus the patients in the control group (not taking AD or AN). T-test p=0,090.

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