Physiological distress predicts surgical risk complications: Analysis of heart rate variability in the pre and post-operative period

Area de investigação médica Physiological distress predicts surgical risk and complications: analysis of heart rate variability in the pre and post-operative period Filipa Raquel da Silva Fidalgo Guimarães Instituto de Ciências Biomédicas Abel Salazar Email: [email protected] Orientador: Prof. Doutor Gil Filipe Ramada Faria Assistente Hospitalar de Cirurgia Geral – Unidade 1 – Cirurgia Digestiva – Serviço de Cirurgia Geral, Centro Hospitalar do Porto Professor Auxiliar Convidado a 30% do Instituto de Ciências Biomédicas Abel Salazar Porto 2015 On Saturday, I was a surgeon in South Africa, very little known. On Monday, I was world renowned. Christiaan Barnard A ideia para este estudo surgiu no serviço de urgência, acompanhando o Prof. Dr. Gil Faria, já que a vontade em realizar a tese de final de mestrado em cirurgia era uma certeza. O gosto por querer saber mais sobre cirurgia surgiu nas aulas com este professor fantástico, que proporciona aos alunos uma filosofia de “aprender ao fazer”, pela paixão pela sua profissão que nos contagia e pela capacidade de fazer qualquer aluno acreditar que há muito mais para descobrir e que qualquer um de nós o poderá fazer. Foi aqui que surgiu a ideia: Porque não tentar descobrir algo agora? E se fosse a minha tese? Estas foram só algumas das razões pelas quais decidi que o fim destes 6 anos de curso teriam que ser terminados em grande, em cirurgia. Este estudo representa uma ideia, uma suposição, de que talvez fosse possível associar a agressão cirúrgica a uma medida de complexidade que pouco havia sido estudada, e nunca em cirurgia. Foi desde logo entusiasmante, havia a possibilidade de fazer a diferença. Apesar de imediatamente apaixonante, a logística que envolveu o presente estudo foi difícil, tanto a nível técnico, como na disponibilidade dos doentes. No entanto a disponibilidade de médicos e enfermeiros do serviço de Cirurgia 1 foi crítica para que este trabalho ganhasse vida. Por outro lado, e acontecendo paralelamente, é sabido que o ultimo ano do estudante de medicina não é fácil. Foi difícil conjugar o estudo que tanto caracteriza este ano, e ainda o estudo e o tempo para que esta investigação acontecesse, mas foi possível e não poderia estar mais contente. Não conseguiria imaginar, nem quereria, que este percurso terminasse de outra forma. Este trabalho representa o fim e um início, com tudo aquilo que de melhor a medicina me pode proporcionar: Trabalho, paixão e vontade. Contents Abstract .............................................................................................................................................. 6 Introduction .................................................................................................................................... 6 Methods ......................................................................................................................................... 6 Results ........................................................................................................................................... 6 Conclusion ..................................................................................................................................... 7 Key words .......................................................................................................................................... 7 Resumo .............................................................................................................................................. 8 Introdução ...................................................................................................................................... 8 Métodos ......................................................................................................................................... 8 Resultados ..................................................................................................................................... 8 Conclusão ...................................................................................................................................... 9 Background ..................................................................................................................................... 10 Materials and Methods .................................................................................................................. 12 Results ............................................................................................................................................. 13 Discussion ....................................................................................................................................... 19 Conclusion ....................................................................................................................................... 22 Acknowledgements ........................................................................................................................ 23 References ...................................................................................................................................... 24 Table index Table I – Patients’ characterization ............................................................................................... 13 Table II - Population characteristics (Pre-operative parameters) ........................................... 13 Table III - Tests of Normality ......................................................................................................... 14 Table IV - Heart rate variability on days 0, 1 and 3 (median values) ..................................... 15 Table V - Tests of Normality (HRV) ............................................................................................. 15 Table VI - Basal HRV according to patients’ characteristics ................................................... 16 Table VII - Change in HRV (Delta SDANN) according to patients’ characteristics .............. 17 Table VIII - Correlation between SDANN and HR ..................................................................... 17 Table IX - Differences between patients with gastric or colonic surgery ............................... 18 Table X – Correlations between D0 HRV (SDANN) and BMI, Age and Blood pressure .... 18 Figure índex Figure I – P-P plots for age and C-reactive protein exemplifying a normal and a nonnormal distribution. ......................................................................................................................... 14 Figure II - Change in SDANN (two-way ANOVA with Greenhouse-Geissler correction) .... 16 Abbreviations list BMI – Body mass índex C-RP – C-reactive protein Hgb - Haemoglobin HR – Heart rate HRV – Heart rate variability ULF - Ultra low frequency VFC – Variação da frequência cardíaca VLF - Very low frequency WBC – White blood cells 6 Abstract Introduction Heart rate variability (HRV) has been studied as a predictor of death and morbidity in trauma and sepsis. Surgery, as sepsis and trauma, is also an aggression to the organism. Our goal was to study heart rate variability after major abdominal surgery. Our hypothesis is that patients would suffer a decrease in HRV after major abdominal surgery. Methods We collected clinical and demographic data from 20 random patients. Continuous R-R intervals (in milliseconds) were recorded using a commercial Suunto Ambit R2 watch in the day before surgery and in the 1st and 3rd post-operative days, for 2 hours. HRV was calculated from the analysis of the continuous R-R monitoring and was processed to eliminate artefacts and cut to uniform the length of the signals. Patients with pace-makers or under B-blocker therapy were excluded from the study. Results The presence of comorbidities, such as, high blood pressure, type 2 diabetes mellitus, smoking habits, and globally the Charlson comorbidities score, were non-significantly related to lower levels of pre-operative HRV. This is reinforced by the association of higher POSSUM and APACHE II scores with lower levels of HRV. The balance of the cardiovascular system was related to HRV: heart rate on day 1 was inversely correlated with HRV (p=0.05) and higher diastolic blood pressure related with increased HRV. (p=0.04). Patients proposed to gastric surgery had lower HRV values (explained by the severity of the disease and general state of the patients) HRV declined significantly in the 1st post-operative day, and recovered to baseline values on the 3rd day after surgery. 7 Conclusion HRV measurement correlated with validated risk scores for surgical patients, identifying patients at higher risk of mortality, intra and post-operative complications. Our preliminary report confirms that major abdominal surgery results in an early decrease in HRV. Most patients recover to baseline values by the 3rd post-operative day. This finding might lead to a novel field of research of the physiologic impact of surgery and to evaluate its relation with surgical risk and complications. Key words Surgery, major abdominal surgery, surgical stress, heart rate variability. 8 Resumo Introdução A variabilidade da frequência cardíaca (VFC) tem vindo a ser estudado como preditor de mortalidade e morbilidade no trauma e na sepsis. Assim como estas duas entidades, a cirurgia também constitui uma agressão ao organismo. O nosso principal objetivo foi estudar a VFC após cirurgia abdominal major. A nossa hipótese é que a VFC diminui após cirurgia abdominal major. Métodos Foi recolhida informação clinica e demográfica de 20 doentes. Utilizando um relógio comercial Suunto Ambit R2, foram adquiridos intervalos R-R consecutivos (em milissegundos) durante 2 horas, no dia antes da cirurgia (dia 0) e nos dias 1 e 3 de pósoperatório. A VFC foi calculada através da análise dos intervalos R-R após o processamento prévio do sinal, eliminando artefactos e uniformizando a duração dos sinais de todos os indivíduos. Doentes com pace-maker ou sob terapia beta bloqueadora foram excluídos do presente estudo. Resultados A presença de comorbilidades, nomeadamente hipertensão arterial, diabetes mellitus tipo 2, hábitos tabágicos e o score de comorbilidades de Charlson, associaram-se de forma não significativa a níveis basais mais baixos de VFC. Estes dados são suportados pela associação de valores mais altos dos scores POSSUM e APACHE II a valores mais baixos de VFC. O equilíbrio do sistema cardiovascular associou-se à VFC: demonstrou-se uma relação inversa entre a VFC e a frequência cardíaca do dia 1 (p=0.05) e direta com a pressão arterial diastólica (p=0.04) Os doentes propostos para cirurgia gástrica apresentaram valores mais baixos de VFC (o que se explica pela severidade da doença e pelo estado geral dos doentes). A VFC diminuiu significativamente no 1º dia de pós-operatório com recuperação para valores basais no 3º dia após a cirurgia. 9 Conclusão A medição da VFC correlacionou-se com scores de risco validados para doentes cirúrgicos, identificando aqueles com maior risco de mortalidade e de complicações intra e pós-operatórias. Este estudo preliminar confirma que a cirurgia abdominal major resulta em diminuição precoce da VFC, sendo que a maioria dos doentes recupera para valores basais ao 3º dia do pós-operatório. Este estudo poderá contribuir para o desenvolvimento de um novo campo de investigação no impacto fisiológico da cirurgia e na avaliação da relação entre a VFC e o risco cirúrgico e as complicações pós-operatórias. 16 Table VI - Basal HRV according to patients’ characteristics Although not statistically significant, patients with higher comorbidities and risk scores, had lower HRV values. Analysis of the SDANN (HRV measure) change between days 0 and 1 is presented in Figure II. Figure II - Change in SDANN (two-way ANOVA with Greenhouse-Geissler correction) Yes No Day 0 SDANN (Mean ± STDev) p Female 51 ± 26,4 52 ± 19.8 0.961 Active smoking 62 ± 23,5 51 ± 10.4 0.514 High Blood Pressure 45.5 ± 22.9 55.4 ± 22.5 0.368 Type 2 Diabetes Mellitus 33.3 ± 19.8 55.2 ± 21.9 0.127 Age > 65 53.74 ± 29.45 49.96 ± 15.46 0.727 BMI >25 48.54 ± 21.04 53.66 ± 10.49 0.630 Co-morbidities 51.22 ± 23.99 54.61 ± 15.73 0.819 Surgeries Gastric surgery 49.1±16.9 53.3±25.9 0.712 APACHE >8% 47.7 ± 17.38 57.7 ± 21.85 0.417 POSSUM >0.8% 49.94 ± 20.72 56.43 ± 25.78 0.402 Charlson > 26% 33.34 ± 19.79 55.20 ± 21.86 0.127 p=0.05 p=0.05 17 Table VII - Change in HRV (Delta SDANN) according to patients’ characteristics Yes No Delta SDANN (Mean ± STDev) p Female -12.36 ± 26.53 -10.21 ± 18.83 0.848 Active smoking -36.33 ± 14.45 -7.87 ± 20.95 0.086 High Blood Pressure -7.72 ± 13.03 -12.68 ± 25.26 0.686 Type 2 Diabetes Mellitus -5.46 ± 18.06 -12.46 ± 23.22 0.634 Age > 65 -8.79 ± 29,69 -12.93 ± 16.41 0.716 BMI >25 -8.85 ± 12.09 -9.21 ± 29.29 0.979 Co-morbidities -7.39 ± 21.64 -29.07 ± 16.41 0.126 Surgeries Gastric surgery -8.00 ± 21.24 -13.48 ± 23.46 0.630 Laparoscopic surgery -15.72 ± 20.54 -7.22 ± 23.78 0.446 APACHE >8% -6.31 ± 29.15 -17.33 ± 18.83 0.399 POSSUM > 0.8% -5.27 ± 26.34 -16.66 ± 19.55 0.337 Charlson > 26% -5.46 ± 18.06 -12.46 ± 23.22 0.634 The change in HRV, although not statistically significant was greater in female patients, active smokers and in laparoscopic surgery. Patients with higher risk scores, had lower change in SDANN on day 1. - Table VII Table VIII - Correlation between SDANN and HR D0 SDANN D1SDANN D3SDANN HR day 0 Correlation -0.197 -0.186 0.355 p 0.419 0.459 0.257 HR day 1 Correlation -0.190 -0.472 -0.629 p 0.451 0.05 0.03 HR day 3 Correlation -0.095 -0.241 -0.240 p 0.709 0.352 0.477 There is an inverse relation between HR in day 1 and SDANN (p=0.05). - Table VIII 18 Table IX - Differences between patients with gastric or colonic surgery Gastric Colonic Mean (SD) / n(%) p Female 4 (57%) 3 (46%) 0.660 Active smoking 1 (14%) 1 (8%) 0.660 High Blood Pressure 1 (14%) 7 (52%) 0.069 Type 2 Diabetes Mellitus 1 (14%) 2 (15%) 0.951 Age 65.77 ± 12.83 60.53 ± 17.25 0.492 BMI 24.25 ± 0.50 26.69 ± 4.39 0.370 Co-morbidities 6 (86%) 11 (85%) 0.951 Hgb 10.97 ± 2.89 13.63 ± 1.97 0.030 C-RP 5.04 ± 8.50 4.18 ± 7.14 0.847 Malignancy 7 (100%) 9 (69%) 0.040 Laparoscopic surgery 1 (14%) 10 (77%) 0.005 APACHE >8% 2 (33%) 2 (17%) 0.453 POSSUM >0.8% 5 (83%) 4 (31%) 0.033 Charlson > 26% 1 (14%) 3 (23%) 0.660 Patients with gastric disease had more often malignant disease, had lower levels of haemoglobin, more laparotomic procedures and higher POSSUM score. Table X – Correlations between D0 HRV (SDANN) and BMI, Age and Blood pressure D0 SDANN Systolic blood pressure Correlation 0.215 p 0.19 Diastolic blood pressure Correlation 0.393 p 0.04 BMI Correlation -0.007 p 0.491 Age Correlation 0.042 p 0.432 Higher diastolic blood pressure in the pre-operative period was correlated with higher levels of HRV. 19 Discussion Heart rate variability is a widely used non-invasive method to determine autonomic activity and its influence on cardiovascular system. HRV represents the imbalance on the autonomic system, decreasing with higher activation of the sympathetic over the parasympathetic system. It is known that it is decreased after cardiac surgery, representing abnormal and insufficient adaptability of the autonomic nervous system. Also, it has been shown to be a predictor of hemodynamic instability and mortality.[22, 23] HRV has also been used to determine deterioration in clinically ill patients. The loss of heart rate variability has been associated with severity and risk of death in sepsis and trauma patients. [16-19] Surgery, as well as these two clinical situations, is an aggression to the organism, inducing an inflammatory response in the post-operative period, with a cardiovascular response characterized by increased heart rate and cardiac output. [4, 6, 9, 10, 12, 15] Biological systems are complex both in structure and in function. In health there is diversity and variety but in disease that range is narrowed such that, according to the chaos theory, healthier systems are the more complex[16]. Measuring complexity is not usually easy and straightforward. There are several methods to measure it: changes on temperature and mobility of the breast were proposed to be associated with breast cancer; respiratory rate variability is higher in younger – healthier – people; and it was proposed that genetic mutations were associated with less complexity in the DNA structure.[24, 25]. In the present study, given its accuracy, ease-of-use, stability on time and reproducibility HRV was used as a marker of systems’ complexity.[23] For the best of our knowledge this is the first study about HRV after major abdominal surgery. Despite the small group of patients evaluated, we can assume that it is representative of the Portuguese adult population. Data from the Portuguese Society of hypertension in 2013 revealed that 42,2% of the Portuguese had high blood pressure (40% in the present study). On the other hand, according to the National Diabetes Observatory in 2012, 12,7% of all Portuguese adults aged 20-79 were diabetic (15% in the present study). Since HRV is variable among different people, we measured individual HRV in the preoperative period establishing the basal value for each patient. [26] 20 Several studies report that older patients have lower levels of HRV. Gender has not been proved to have a significant independent influence and the studies are controversial.[27, 28] Patients with chronic illnesses (such as diabetic neuropathy, congestive heart failure, high blood pressure, sleeping disorders, angina pectoris, or obesity) have lower levels of basal HRV.[20, 23, 29-34] Nutritional habits, such as a high fatty acids diet, tobacco and alcohol habits also have decreased HRV basal levels.[20, 35] Although differences were not statistically significant, our results are concordant with these findings. On the other hand, it is known that HRV is inversely correlated with heart rate – the sympathetic activation which increases heart rate is associated with reduced HRV – though, pharmacological therapies with negative chronotropism, such as Beta-Blockers, are associated with higher levels of HRV.[30] In this study, patients under beta-blockers treatment were excluded. Even if patients’ basal HR and HRV were not correlated in the present study, the fact that HR in day 1 and HRV were correlated, might indicate that under control of the sympathetic autonomous system, both HR and HRV suffer a change after abdominal surgery. In fact, HRV seemed to be a good measure of the more subjective “frailty”. It has a probable correlation with the presence of co-morbidities, which underlines that HRV measurement and the systems’ complexity are in fact, associated with more severe disease and less entropy. Despite the lack of significance, HRV measure was consistently lower in patients with smoking habits, high blood pressure and type 2 diabetes mellitus when compared with patients without those comorbidities. Furthermore, the unspecified presence of co-morbidities, was also related to lower baseline HRV. To underline this findings, patients with higher risk in pre-operative scores, such as Charlson comorbidities and POSSUM, have decreased HRV. We also found differences between HRV according to the organ affected. Patients with gastric disease had lower levels of SDANN in the pre-operative period when compared to colon disease. Despite the lack of statistical relevance, this tendency could be explained by the differences between the illnesses and its diagnosis. Gastric cancer is usually found at an advanced stage, when the patients have lost weight and present constitutional symptoms, while colorectal cancer patients are usually diagnosed by screening colonoscopies.[36, 37] Overall, patients with gastric surgery seem to be more frail and with a more advanced disease burden. In fact, when comparing both gastric and colonic patients, we found that patients with gastric disease had lower levels of haemoglobin 21 (p=0.03), were more often malignant (p=0.04), had higher POSSUM score (p=0.03) and the preferred surgical approach was laparotomy (p=0.005). There was no significant correlation between SDANN in the pre-operative period and preoperative measurements, such as vital signs or age. Higher levels of diastolic blood pressure are associated with higher levels of HRV (p=0.04). In fact, diastolic blood pressure is mainly affected by the autonomous nervous system. Higher parasympathetic activation is related to higher levels of diastolic blood pressure and with higher levels of HRV.[38] The lack of significant associations between HRV and some of the patients’ characteristics might be due to the small size of the sample and to its heterogeneity. Only a greater sample will allow for a more robust and multivariable analysis of the relations between HRV and patient characteristics. Since major surgery is an aggression to the organism and it disrupts the normal physiologic functions, it was expected that HRV would decrease after major surgery. The most important result of this study is that, in fact, there is a significant decrease in complexity (HRV) in the first post-operative day. The recovery of the “normal physiology” happened by the 3rd post-operative day, with patients resuming their baseline HRV. HRV recovery after cardiac surgery has been widely variable: some patients recover in a few days and others can still be recovering to basal HRV one year after surgery.[23, 39] In our study, patients recovered to their basal levels by post-operative day 3. We did not identify which factors would predict HRV recovery (or magnitude of decrease after surgery), but this might be a novel path of research in surgical physiology. Although the number of patients studied and the number of complications occurred after surgery did not allow us to study the impact of HRV on surgical complications, patients with higher pre-operative risk assessment (using the POSSUM score), higher risk of inhospital mortality (using APACHE II) and higher risk of 1-year death (Charlson comorbidities score) had lower baseline levels of HRV. Although this difference did not reach statistical significance, these associations are plausible and warrant further research. 22 Conclusion As hypothesized HRV is a good measure of frailty, being non-significantly associated with comorbidities, such as type 2 diabetes mellitus, high blood pressure and smoking habits. Also, risk scores such as POSSUM, APACHE II and Charlson comorbidities score had a non-significant association with HRV. HRV was associated with variations on cardiovascular measures, such as heart rate and blood pressure. There is an inverse relation with heart rate, which represents the disproportional activation of the sympathetic nervous system. On the other hand there is a direct relation with diastolic blood pressure, which is mainly affected by the parasympathetic nervous systems, proving its protective function on the cardiovascular system. Patients with gastric disease had significant lower levels of haemoglobin, more malignant disease, higher APACHE II score and higher need for laparotomic surgery, confirming the frailty of these patients. Non-significant lower levels of HRV were found in patients proposed to gastric surgery. The main conclusion is that HRV decreases on day 1 after major abdominal surgery, recovering to baseline on day 3. This finding might lead to a novel field of research of the physiologic impact of surgery and to evaluate its relation with surgical risk and complications. 23 Acknowledgements Agradeço ao meu tutor, o Prof. Dr. Gil Faria, por ter sido um verdadeiro orientador, pela sua disponibilidade e ajuda incondicional. Mais do que tudo, por me ter apresentado uma cirurgia diferente e por me ter feito apaixonar por ela, de forma que nenhum outro professor o fez em 6 anos. Ao Prof. Dr. Jorge Santos, Dr. Pedro Moreira, Dr. Bruno Santos, Dr.ª Sílvia Pereira e, de uma forma geral, a toda a equipa medica e de enfermagem do serviço de Cirurgia 1 do CHP-HSA. Sem a vossa disponibilidade e ajuda este trabalho não poderia ter sido feito. Também um grande agradecimento à Prof. Dr.ª Carla Quintão do departamento de Física da Universidade Nova de Lisboa e ao seu aluno Filipe Valadas que foram fundamentais para o desenvolvimento deste estudo. Agradeço também à minha família, aos meus amigos e ao meu namorado, todo o apoio incondicional, não só agora, mas sempre. This article has been sent to publication. 24 References 1. World Health Organization. Surgery. 2008. 2. Estatística, I.N.d., Anuário Estatistico de Portugal 2011. 2012: Instituto Nacional de Estatistica. 3. Giannoudis, P.V., et al., Surgical stress response. Injury, 2006. 37: p. S3-S9. 4. Gutierrez, T., R. Hornigold, and A. Pearce, The systemic response to surgery. 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