Factors related to loss of appetite in postoperative cardiac surgery patients: A systematic review [version 1; peer review: 1 approved with reservations]

Background: Postoperative cardiac surgery patients often experience appetite loss. Although nutritional status is known to be associated with time of recovery, functional status, and length of stay, less is known about factors related to patient’s loss of appetite after cardiac surgery. This review aimed to identify and understand factors related to loss of appetite in postoperative cardiac surgery patients , systematic review with narrative summary design was applied. Data sources including CINAHL, SCOPUS, PubMed, ProQuest, ScienceDirect, ThaiLIS, ThaiJo, and E-Thesis were searched without restriction on publication year through August 2020. Methods: We conducted the review following the Joanna Briggs Institute methodology, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist to categorize methodological quality and the PRISMA flow diagram to record the studies’ factors. Results: Six studies reported one or more of 16 factors related to loss of appetite: older age, sex (female), illiteracy, history of chronic disease, not knowing someone in health field, pain score ≥ 7, pain medications containing codeine, constipation, depression, heart-lung machine ≥ 120 minutes, preoperative serum creatinine levels ≥ 179 µmol/L, emergency surgery, perfusion pressure ≤ 40 mmHg, low cardiac output syndrome, mechanical ventilation ≥ 96 hours, and a New York Heart Association class III and IV.


Introduction
Heart disease is one of the leading causes of death in both developed and developing countries 1 .Although treatment depends on severity and types of heart disease, first line approaches include lifestyle changes involving nutrition, exercise, and medication.As patients' symptoms worsen or complications increase, cardiac surgery often becomes the next treatment of choice 1 .
There are various types of cardiac surgery.These include coronary artery bypass graft, valve replacement and repair, great vessel surgery, and septum repair for those with congenital heart disease.Most of these surgeries require the use of the heart-lung machine as a cardiopulmonary bypass to take over the function of the heart and lungs during surgery to help surgeons repair a diseased heart's malfunctioning.Because there have been adverse effects from using the heart-lung machine on the various body systems, an off-pump coronary artery bypass technique was developed as an alternative 2 .Nevertheless, the cardiopulmonary bypass remains widely used during open heart surgery.Prevention and management of possible deleterious effects from its use require ongoing assessment.

Background
Alterations in postoperative physiological/psychological functioning contribute to loss of appetite.Surgery and the use of the heart-lung machine cause injuries in tissues and peripheral nerves that can lead to a nociceptive and inflammatory response, causing prostaglandins, bradykinins, and substance P to become increased that produces physical pain 3 .Postoperative pain and the use of the heart-lung machine are stressors that produce a physiological response such as the systemic inflammatory response syndrome 3 .The syndrome is a disturbance in the balance of the coagulation system that decreases the production of platelets and fibrinogen with increases in prothrombin time, leading to a higher risk of postoperative bleeding 4 .The immune system responds by decreasing the polymorphonuclear neutrophils and also macrophages in the lungs, which heighten the risk of infections, including pneumonia 5 .Cardiac surgery also intensifies catabolism and insulin resistance, resulting in higher blood sugar levels in both patients with and without a history of diabetes 6 .These factors directly and indirectly disturb the postoperative physiological/psychological interconnections to produce a loss of appetite and a nutritional imbalance 7 .
Food consumption behaviors change when patients consume small volumes of food, coupled with physical decline, less body movement/mobility, depression, and postoperative stress.Ścisło et al. (2019) found that after the cardiac surgery, 50% of patients had loss of appetite with an increased risk of poor nutrition, 35.4% had postoperative complications, and 10% had a decreased body mass index (BMI) 8 .The study affirmed that a decrease in BMI after surgery is associated with postoperative complications 9 .Chermesh et al. (2014) found similarly that poor nutritional status increases the severity and number of complications in postoperative patients 10 .Ringaitienė et al. (2016)  reported that recovery is delayed in patients who have a loss of appetite and consume less food, causing longer hospitalizations 11 .
Based on clinical experiences in caring for patients who had undergone cardiac surgery, we observed that some patients had decreased appetite, difficulty eating, ate less or had early satiety, and suffered bouts of nausea and vomiting.We further observed that these same postoperative cardiac surgical patients tended to have a late recovery, longer duration of hospitalization, and poorer prognosis than others without the symptoms.To the best of our knowledge, we found no literature that summarized and explained our observations.Therefore, the purpose of this systematic review of the literature was to contribute to a body of knowledge by focusing on all known factors related to loss of appetite in postoperative cardiac surgery patients.Understanding these factors will provide a foundation that is necessary to support nursing practice of cardiac surgical patients and inform future researchers what further aspects of loss of appetite need to be studied.

Purpose
The purpose of this review was to systematically identify and understand the collective factors related to loss of appetite in postoperative cardiac surgery patients as found in published research.

Design
We followed the systematic review process with narrative summary as prescribed by the Joanna Briggs Institute (JBI) methodology by formulating the review question, defining the inclusion and exclusion criteria, developing the search strategy, locating and selecting studies, assessing their quality, extracting data, and analyzing and interpreting the results 12 .Moreover, the protocol for systematic review was registered at PROS-PERO on February 1, 2021 and registration number was CRD42021234615.

Search methods
We searched CINAHL, SCOPUS, PubMed, ProQuest, ScienceDirect, ThaiLIS, ThaiJo, and E-Thesis databases and used snowballing through reference lists of defined studies.The search for both English and Thai published papers was made without restriction on publication year through August 2020.The search strategy used the keywords "cardiac surgery" OR "open-heart surgery" AND "poor appetite" OR "loss of appetite" OR "decreased appetite" OR "change in appetite" OR "anorexia."The selection of studies was made based on the following inclusion criteria: (a) research in humans related to cardiac surgery; (b) results about factors related to loss of appetite in postoperative cardiac surgery patients; (c) patients aged 18 years and older; and (d) published in the English or Thai language.
Search outcomes There were 5,774 original studies from the databases and two from hand searches.The winnowing process began with deduplication, which left 3,320 studies.Only 74 studies had full-text availability, of which 68 were excluded because they did not fully meet the inclusion criteria.As a result, six empirical research articles remained for appraisal.Figure 1 displays the PRISMA flow diagram of the information flow during the review process.

Quality appraisal
We individually reviewed the six selected articles using the standardized critical appraisal instrument from the JBI for analytical cross-sectional studies 13 .The studies were required to meet a positive response (i.e., "yes") on a minimum of four of the eight questions on the critical appraisal tool.Methodological quality was grouped into the four categories of very low, low, moderate, and high quality.

Data abstraction
On the JBI data extraction form (Aromataris & Munn, 2018) 12 , we recorded the studies' authors, study designs, settings, participants, levels of evidence certainty and methodological quality, types of surgery, times of outcomes measuring, and factors related to loss of appetite.Prior to starting the review, we practiced article screening, data extraction, and quality assessment with two other researchers who independently verified that the process and results we had undertaken were accurate.If there were incongruent opinions during the actual review process, we reached consensus in mutual discussion.

Synthesis
Extraction of quantitative data to conduct meta-analysis was not possible due to the heterogeneity of the study population, different types of cardiac surgery, outcome measures, and data analysis across the studies.The findings have been presented and discussed in tabular and narrative form to aid the data presentation.

Results
Six research articles met the inclusion criteria [14][15][16][17][18][19] .They were all descriptive studies.Five had a moderate level of quality, and one had a high level of quality (Table 1 & Table 2).Two studies were published before the year 2000 16,17 , and four were published on or after 2000 14,15,18,19 .Patients in five studies had undergone coronary artery bypass graft surgery 14,[16][17][18][19] ; patients in three studies had undergone valve surgery 15,16,19 ; and patients in one study had both a septum repair for congenital heart disease and a repair of the aorta 19 .The surgeries reported in five studies required cardiopulmonary bypass [14][15][16]18,19 , whereas one study did not specify its use 17 . Althogh five studies addressed patients postoperatively and after-discharge [14][15][16][17][18] , one study described the preoperative, operative, and postoperative phases 19 (Table 3).19 reported specifically that the patient's sex and types of cardioplegia solutions had no impact on loss of appetite in postoperative cardiac surgery patients (Table 3).

Discussion
We found that there were 16 factors related to loss of appetite in cardiac surgery patients.They were present in the preoperative, operative, or postoperative/discharge phases.

Preoperative phase
The aging process in itself can produce a loss of appetite due to a decrease in taste and smell, resulting in discontent with eating and a poor appetite 20 .Older people (≥ 60 years) experience a decrease in ghrelin or a hunger hormone, an increase in leptin and insulin, and changes in the gastrointestinal system and inflammatory process, such as an increase in interleukin 1 (IL-1) and 6 (IL-6) and tumor necrosis factor alpha (TNF-α) 21 that contribute to a loss of appetite.Older females, with low estrogen levels transitioning through menopause or post menopause can also have a loss of appetite 20 .Whether males or females are more likely to have a loss of appetite with cardiac surgery, however, needs further study, since Zang et al. (2009) found there was no statistical difference between the two 19 .Chronic disease, such as diabetes or hypertension, can lead to an inflammatory process and an increase in interleukin and tumor necrosis factor alpha, which are known to be related to appetite 22,23 .Moreover, increased blood sugar and high blood pressure can produce physiological stress.Both may directly and indirectly cause loss of appetite by pathophysiological and psychological pathways 7 .
Illiterate patients and those who do not know someone in the health field tend to experience loss of appetite.They may be less knowledgeable and unsure of self-care activities or uncomfortable and inexperienced in seeking help with their health and nutrition problems.Cebeci and Celik (2008) and Choocherd et al. (2016) also found that low health literacy was related to nutritional problems in coronary artery bypass graft surgery patients 24,25 .High preoperative serum creatinine also affects loss of appetite, but indirectly 24,25 .A decline in glomerular filtration is associated with reduced food intake [26][27][28] .Although hospitals are not traditionally known for tasty cuisine, prolonged lengths of stay in an intensive care unit can produce depression that may lead to a lack of appetite 26,29,30 .

Operative phase
During the use of the heart-lung machine, chemical substances are produced by a systemic inflammatory response named proinflammatory cytokine 31 .This substance includes interleukin (IL), tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ) and granulocyte-macrophage colony stimulating factor (GM-CSF).Higher levels of chemical substances are strongly related to loss of appetite.These chemical substances also become substantially increased in patients with cancer, affecting appetite.After the heart-lung machine is disconnected, the substances can remain at high levels for 48 hours after surgery 32 .Not only does the heart-lung machine produce a systemic inflammatory response, but the digestive system is interrupted.Prolonged use of the heart-lung machine can lead to weariness and loss of appetite after cardiac surgery 32 .
Low cardiac output syndrome, low perfusion pressure, and emergency surgery may indirectly affect loss of appetite.These three factors correlate with extended stays in the intensive care unit, total lengths of hospitalization, and prolonged intubation times 26,28 .Low cardiac output and low perfusion pressure place patients at risk of acute kidney injury that can lead to high serum creatinine; and emergency cardiac surgery causes more postoperative complications in patients than planned surgery 26,27,33 .These three conditions may collectively bring about stress and depression, leading to loss of appetite 26,29,30,34 .

Postoperative phase
Prolonged mechanical ventilation requires suctioning patients' endotracheal tubes to clear the airway, leading to postextubation fatigue and loss of appetite.It is a significant factor affecting patients' appetite levels after their endotracheal tubes are removed.Longer periods of postoperative mechanical ventilation are also influenced by higher levels of preoperative creatinine, low cardiac output, and psychological depression, further contributing to loss of appetite 35 .Depression itself is a source of appetite loss by the hypoactivation of the brain's insular regions, especially mid-insular cortex that supports the body's physiological control of eating 36 .Depressed patients have an increase in their hypothalamic-pituitary-adrenal drive that can cause high levels of cortisol, which is associated with decreased appetite and hypoactivation of food-motivation neurocircuitry 30,34,37 .The interactivity and interaction among these regions, however, contribute to individual differences in patients with depression-related appetite changes 36 .
After open heart surgery, patients experience pain and discomfort during routine postoperative care, such as deep breathing and coughing to expand the lungs and clear secretions, using an incentive spirometer, moving/turning in bed coupled with early ambulation, and undergoing physical therapy with possible rehabilitation activities.Pain decreases the movement and mobility of patients, so the stomach and intestine are relatively less functional 38 .Patients can feel anxious, insecure, and uncertain about the disease and success of the surgery, causing them to have emotional stress.These complicated reactions are intercorrelated and can affect the appetite directly and indirectly.As a result, these patients may experience a decrease in appetite with a distorted perception of smell and gustatory dysfunction, leading to a lower consumption of food 39 .
Pain that occurs immediately after cardiac surgery is called acute pain, whereas pain after hospital discharge is chronic pain.Both can stimulate the inflammatory process, which causes the release of cytokine, especially IL-6 40,41 .Interleukine-6 is related to loss of appetite.Because the release of cytokine leads to the pain cycle, postoperative patients require analgesics, usually with codeine 42,43 .Medications containing codeine coupled with less physical movement and stomach/intestinal dysfunction may cause constipation.Constipation affects loss of appetite because patients feel that food remains in the gastrointestinal system, which produces abdominal discomfort 38,44 .
Patients with NYHA Class III & IV heart failure may have a loss of appetite due to hypervolemia, especially if there is congestion in the lungs, liver, and intestine 45 .Congestion directly affects the function of the respiratory and gastrointestinal systems, producing dyspnea, fatigue, and inactivity, all related to loss of appetite.Liver and intestinal congestion leads to gastrointestinal hypomotility of the stomach and intestine 46 .This may cause abdominal distension and discomfort, thus inhibiting patient activities would stimulate appetite.In addition, medications that treat and control heart failure, such as digoxin and simvastatin, not only impact appetite indirectly by affecting the function of the gastrointestinal system but also decrease appetite directly 46,47 .
Five out of the six studies had a moderate level of methodological quality 14,[16][17][18][19] .The researchers did not report their confounding factors, missing data, or how they managed the statistical challenges.Only one study (Correâ & Cruz, 2000)  reported controlling for two confounding factors that may have affected loss of appetite (i.e. level of pain and onset of having pain) 15 .Pain is both a rapidly (state variable) and slowly (trait variable) changing factor 48,49 .A state variable can change in a short time period and at a specific moment, whereas a trait variable takes much longer to change.Correâ and Cruz (2000) divided  The research provides a very good indication of the likely effect.The likelihood that the effect will be substantially different is low.
Moderate: The research provides a good indication of the likely effect.The likelihood that the effect will be substantially different is moderate.
Low: The research provides some indication of the likely effect.The likelihood that it will be substantially different (a large enough difference that it might have an effect on a decision) is high.Very low: The research does not provide a reliable indication of the likely effect.The likelihood that the effect will be substantially different (a large enough difference that it might have an effect on a decision) is very high.the samples into several groups based on the level and onset of pain and compared the differences of loss of appetite between each group to identify more clearly the factors related to loss of appetite 15 .Because only one of the six studies demonstrated high methodological quality by controlling for confounding factors, we cannot make firm conclusions on the overall results of the systematic review 12 .
Some of the 16 factors we report are not exclusive to postoperative cardiac surgery patients.Other types of surgery can produce changes in eating behaviors, food intake, loss of appetite, and malnutrition in postoperative patients.Factors may include older age 50,51 ; sex (female) [50][51][52] ; type of illness or chronic disease, such as type 2 diabetes mellitus 50,52 ; medications 50 ; length of hospital stay 50 ; and psychological factors, such as stress, depression, psychopathology, and well-being 53 .In addition to those reported for general surgery patients, our systematic review expanded knowledge of other specific factors related to loss of appetite in postoperative cardiac surgery patients.

Strengths and limitations
We searched extensively the published literature in eight national and international databases, restricting the studies to those in English or Thai.Out of a large potential number of studies, only six met the specific criterion related to loss of appetite in postoperative cardiac surgery patients [14][15][16][17][18][19] .None of the studies had loss of appetite as a primary research objective.Methodological problems in some studies could have been strengthened by having larger sample sizes, reporting how missing data were handled, and mentioning how confounding factors were controlled 14,[16][17][18][19] .In the studies with a larger sample size, subgroup analysis on individual factors could have brought better understanding of their influence on loss of appetite 19 .None of the six studies used an experimental research design and long-term evaluation.

Conclusions and implication
This systematic review 54 provides initial knowledge for the development of nursing interventions based on the factors related to loss of appetite in postoperative cardiac surgery patients.Clinical assessment by nurses and other health professionals should include whether patients were on the heart-lung machine ≥ 120 minutes, had emergency surgery, reported having a low cardiac output syndrome, or required mechanical ventilation ≥ 96 hours.To promote patient's nutritional status, there should be evidence-based practice guidelines on the management of postoperative symptoms related to loss of appetite.These would include pain management, treatment of constipation, and reduction of emotional stress and depression.Additional information on self-care should be given to patients and families before hospital discharge to relieve their stress and depression, enhance knowledge of nutrition to promote healing, and prevent loss of appetite.However, nurses and health professionals should first assess health literacy to ensure that patients and families adequately understand the discharge instructions.
Discharge planning should provide instruction on how to support self-care ability and reduce post-discharge problems, especially guidance in nutrition after coronary artery bypass graft surgery.A multidisciplinary approach, including physician, nurse, dietitian/nutritionist, and pharmacist, should be considered as part of the holistic care given to postoperative cardiac surgery patients because loss of appetite can result from multiple factors that lead to poor nutrition and inhibit healing.
Future research should focus on the identified factors related to appetite loss in postoperative cardiac surgery patients.The use of multiple research methods and longitudinal studies will provide a foundation for evidence-based interventions to reduce loss of appetite and improve nutritional status for patients after cardiac surgery.
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Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Flowchart of the Review Process.
There were 16 factors identified in the six studies related to loss of appetite and they were divided into three phases.The preoperative factors were (a) age ≥ 60 years old; (b) sex (female); (c) history of a chronic disease, such as diabetes, hypertension, hyperlipidemia; (d) illiteracy; (e) not knowing someone in the health field; and (f) preoperative serum creatinine level ≥ 179 µmol/L.The operative factors were (a) emergency surgery; (b) using the heart-lung machine ≥ 120 minutes; (c) perfusion pressure ≤ 40 mmHg; and (d) low cardiac output syndrome.Finally, the postoperative factors were (a) using mechanical ventilation ≥ 96 hours; (b) moderate or higher pain score (≥ 7 points); (c) using pain medications containing codeine; (d) constipation; (e) depression; and (f) New York Heart Association (NYHA) class III and IV.Nevertheless, the study of Zang et al. (2009) Grades of Evidence for certainty of evidenceHigh:

Table 2 . Grading results of the six selected studies from the quality assessment of the evidence by GRADE guideline 13 . Quality Assessment of the Evidence by GRADE Guideline No.
b Precision (