Article Text
PDF
Abstract
Objective Postoperative delirium (POD), especially after cardiac surgery with cardiopulmonary bypass (CPB), is a relatively common and severe complication increasing side effects, length of hospital stay, mortality and healthcare resource costs. This study aimed to determine the impact of using mannitol serum in the prime of CPB for preventing the occurrence of delirium in patients undergoing coronary artery bypass surgery.
Methods This study is a single-centre, double-blinded, randomised, controlled trial that was conducted from December 2022 to May 2023. Patients in the age range of 18–70 who underwent elective coronary artery bypass surgery were included in the study. In the control group (n=45), the prime solution included Ringer’s lactate serum. In the intervention group (n=45), the prime solution consisted of 200 mL mannitol serum and Ringer’s lactate serum. The primary outcome of the study was the incidence of POD. Secondary outcomes included the duration of mechanical ventilation, length of stay in the intensive care unit (ICU) and 30-day in-hospital mortality.
Results There were no statistically significant differences in demographic characteristics and risk factors between the control and intervention groups (p<0.05). However, the incidence of POD was significantly lower in the intervention group compared with the control group (22.25% vs 42.2%, p=0.035). There were no significant differences between the two groups regarding CPB time, aortic cross-clamp time, duration of mechanical ventilation and length of stay in ICU (p<0.05). Additionally, mortality rates and rates of return to the operating room did not differ significantly between the two groups (p<0.05).
Conclusions This study concluded that adding mannitol to the prime of CPB pump can help reduce the incidence of delirium after cardiac surgery.
Trial registration number IRCT20221129056660N1.
- Coronary Artery Bypass
- Cardiac Surgical Procedures
- Heart, Artificial
Data availability statement
Data are available on reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
WHAT IS ALREADY KNOWN ON THIS TOPIC
Delirium after cardiac surgery can lead to longer hospital stays, higher rates of complications and increased risk of death.
Identifying risk factors and taking preventive measures is crucial to reduce the incidence of postoperative delirium.
Risk factors may include advanced age, pre-existing cognitive impairment, electrolyte imbalances and certain medications.
Preventive strategies can involve optimising pain management, promoting early mobility, maintaining hydration and minimising the use of medications that can contribute to delirium.
WHAT THIS STUDY ADDS
Adding mannitol to the cardiopulmonary bypass solution can effectively reduce delirium following cardiac surgery.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This information may assist physicians and perfusionists in selecting the optimal combination of priming for cardiopulmonary bypass.
The findings of this study could present an effective strategy for reducing delirium after heart surgery.
This study was conducted solely on adult patients undergoing coronary artery bypass grafting, highlighting the need for similar research in other cardiac surgeries, such as those involving children.
Introduction
Postoperative delirium (POD) is a relatively common and serious complication,1 the occurrence of which is reported to be about 20% in non-cardiac surgery patients.2 The occurrence of delirium after cardiac surgery is more common than that after other surgeries and has been reported at 20%–55%.3 4 POD can increase side effects, leading to more extended hospital stays, higher mortality rates and added healthcare resource costs.1 5
Several theories have been proposed regarding the causes of POD, including neuroinflammation, changes in neurotransmitters and subclinical vascular events in the brain.1 Cardiopulmonary bypass (CPB) and its duration are also considered a factor of delirium following cardiac surgery.6 Rapid changes in temperature, intravascular pH and arterial pressure during CPB can induce a significant inflammatory response that affects cerebral perfusion, uptake and patient oxygen consumption. Consequently, brain tissue may experience hypoxia and ischaemia.6 7 Other causes of delirium include increased intracranial pressure and decreased cerebral blood flow due to haemodilution.8 9
A rise in intracranial pressure leads to a decrease in cerebral perfusion pressure and, more importantly, cerebral blood flow, which may result in a disturbance in the level of consciousness and manifest as delirium.9
Hyperosmolar solutions, such as mannitol, can be used in CPB priming to help balance fluids and osmolality. This can effectively reduce the haemodilution effects that occur during CPB.10 11 Mannitol is an osmotic diuretic that can improve renal blood flow, minimise excess vascular fluid displacement and reduce the positive fluid balance caused by the priming of the cardiac bypass machine.12 Mannitol can significantly reduce the water content in the central area of oedema, effectively preventing the rapid growth of the oedema area and restoring the cerebral blood flow.13 Also, mannitol infusion can efficiently reduce intracranial pressure.14 Studies have also mentioned the antioxidant effects of mannitol.15 16
Due to its osmotic and antioxidant effects, mannitol can prevent delirium in patients undergoing CPB. Therefore, we designed a randomised controlled trial by hypothesising that adding mannitol for priming the CPB pump can reduce the incidence of POD in patients undergoing coronary artery bypass surgery.
Methods
Our study is a prospective, intention-to-treat, parallel, double-blinded, controlled phase IV clinical trial that was registered in Iranian Registry of Clinical Trials (IRCT20221129056660N1) and the study protocol is detailed in online supplemental file 1. We conducted this study in a single centre (Shahid Madani Hospital) from December 2022 to May 2023. Patients aged 18–70 years scheduled for coronary artery bypass grafting were consecutively screened for eligibility to participate in the study.
The inclusion criteria were an ejection fraction >30% in echocardiography before surgery and normal kidney function, which is defined as an estimated glomerular filtration rate>60 mL/min. Exclusion criteria were as follows: acute surgery within the last 24 hours, a history of cardiac surgery, documented allergic reactions, a body mass index >40 kg/m2, the need for deep hypothermia, severe vision or hearing problems and documented psychiatric or dementia issues.
After explaining the research objectives to the participants, written consent was obtained from them to participate in the study. The participants had the right to withdraw from the survey at any time until the end of the research. The study did not impose any additional costs on the participants. The sample size was calculated using data from Ljunggren et al’s study,11 with a power of 80% and Cronbach’s alpha of 0.05. Accounting for a 25% attrition rate, 45 samples were assigned to each group using the following formula:
Using the sequentially numbered, opaque sealed envelopes method, 90 patients were randomly allocated in a 1:1 ratio into intervention and control groups, with 45 patients in each group. Random allocation sequence was created with a table of random numbers. The person preparing the prime solution selected the envelopes immediately before the patient entered the operating room. Sampling continued until the desired number of samples was reached. All interventions, such as anaesthesia administration and CPB, were performed equally for the two groups without bias. The same surgeon operated on all cases in this study. Only one person was responsible for randomising and preparing the prime pump to keep the content disguised from staff members treating the patient. Throughout the intervention and data collection procedure, colleagues from anaesthesia, surgery, perfusion, nursing and patients were kept blind to the patient groups.
CPB was performed by using a Stöckert S5 roller pump and an INSPIRE 8f membrane oxygenator. Before the operation, one person prepared 200 mL of mannitol 20% for the intervention group and 200 mL of Ringer’s lactate solution for the control group. The serum bottles were covered with an opaque tape.
The pump prime for the intervention group contained 200 mL of 20% mannitol solution, 900 mL of Ringer’s lactate solution, 50 mL of sodium bicarbonate and 5000 units of sodium heparin. The pump prime for the control group contained 1100 mL of Ringer’s lactate solution, 50 mL of sodium bicarbonate and 5000 units of sodium heparin. If there was a volume deficiency during CPB, up to 1000 mL of Ringer’s lactate solution could be added to the circuit.
The tepid St. Thomas solution was injected using the cardioplegia injection system to protect the heart. This study used non-pulsatile flow (2.4 mL/m2) and moderate hypothermia (28°C–32°C). The patient’s blood pressure was maintained within 50–80 mm Hg range throughout the operation, with a hematocrit level of approximately 24%.
Before surgery, basic demographic information of patients such as age, sex, EuroSCORE II, body surface area, history of blood pressure, diabetes and smoking habits was documented. Aortic cross-clamp time and CPB time were also recorded during the operation. Additionally, the duration of mechanical ventilation, length of stay in intensive care unit (ICU) and 30-day in-hospital mortality rates were all documented. Patients in the ICU were sedated using fentanyl and midazolam infusions
The Delirium Observation Screening Scale (DOSS) was used to diagnose delirium, and Koster et al confirmed its validity for patients undergoing cardiac surgery.17 The DOSS describes typical behavioural patterns related to delirium in 13 statements or questions, which the observer has to answer with ‘never’ (score=0) or ‘sometimes or always’ (score=1) if applicable (see box 1). Postoperatively, the nurses applied the DOSS at the end of every shift based on their observations during that shift. A DOS score of N≥3 indicates delirium. Before starting the study, nurses were trained to assess patients for delirium using the DOSS.
The working method of the Delirium Observation Screening scale
The patient dozes off during conversation or activities.
Is easily distracted by stimuli from the environment.
Maintains attention to conversation or action.
Does not finish question or answer.
Gives answers that do not fit the question.
Reacts slowly to instructions.
Thinks to be somewhere else.
Knows which part of the day it is.
Remembers recent events.
Is picking, disorderly, restless.
Pulls intravenous tubes, feeding tubes, catheters, etc.
Is easily or suddenly emotional (frightened, angry and irritated).
Sees/hears things which are not there.
Never=0 points; sometimes or always=1 point. A total score of 3 or more points indicate a delirium.
The hypothesis of this study was tested by comparing the incidence of POD between groups, which determined our primary outcome. Secondary outcomes included ventilation time, ICU length of stay and 30-day mortality. The data were analysed using SPSS software (V.22). The Kolmogorov-Smirnov test was used to assess the normality of the data. Based on the normality, independent t-tests, χ2 tests and Mann-Whitney U statistical tests were used to check for differences and compare the research variables. A p<0.05 was considered to be significant.
Results
A meticulous patient selection process was followed in the course of this study. Out of the initial 107 eligible patients, 3 were excluded due to documented allergic reactions, two due to BMI>40 kg/m2, 8 due to acute surgery within the last 24 hours and 4 due to documented psychiatric or dementia problems. This rigorous approach ensured that the study continued with a robust sample size of 90 patients (45 patients in the intervention group and 45 patients in the control group), which is depicted in figure 1. Importantly, none of the participants was excluded from the study after the start of the intervention, further enhancing the reliability of the findings.
Patients flow chart. CONSORT, Consolidated Standards of Reporting Trials.
As presented in table 1, the demographic characteristics and risk factors were not significantly different between the control and intervention groups (p<0.05), except for blood pressure. This variable, which was considered a confounding factor in the data analysis, was appropriately adjusted (p=0.008). As a result, the studied groups demonstrated a high degree of homogeneity in terms of demographic variables and risk factors. This homogeneity is a crucial aspect of the study design because it ensures that any observed differences in outcomes can be attributed to the intervention rather than to baseline differences between the groups.
Demographic characteristics and risk factors
As shown in table 2, in terms of time parameters, including CPB time, aortic cross-clamp time, time connected to mechanical ventilation and ICU time shown in table 1, no statistically significant difference was observed between the two groups (p>0.05).
Time parameters
As shown in table 3, there was no significant difference in mortality and readmission to operating room between the two groups (p>0.05). However, a statistically significant difference was observed in POD between the intervention and control groups (p=0.035). No significant side effects were observed in the study groups caused by mannitol, either.
Postoperative outcome
Discussion
The results of this study suggest that adding mannitol to prime the CPB can be effective in reducing the incidence of delirium after surgery. The occurrence of delirium after surgery, especially heart surgery, remains one of the most common problems associated with numerous short-term and long-term complications.18–20 Approximately 25% of patients experience delirium following heart surgery,21 which was reported as 19.3% in Hamiko et al’s study,3 36% in Claesson Lingehall et al’s study22 and 52% in Rudolph et al’s study.23
The incidence of delirium following heart surgery may vary due to factors such as previous medical history, type of surgery, postoperative complication rates and different delirium assessment methods. In this study, we used the specialised DOSS tool to assess delirium following cardiac surgery, which has been sanctioned for use in these patients,17 and the overall incidence of delirium was 32.2%. The lack of success in preventing delirium is mainly due to its multifactorial nature. Risk factors for delirium include being over 70 years of age, higher EuroSCORE scores, longer cross-clamp time and high chest drainage.20 Chen et al identified eight risk factors for delirium during their meta-analysis. These factors include age, diabetes, preoperative depression, mild cognitive impairment, carotid artery stenosis,New York Heart Association (NYHA) Functional ClassIII or IV, duration of mechanical ventilation and length of stay in the ICU.18 The risk factors known to contribute to the occurrence of POD following cardiac surgery are also indicators of extended duration and substantial overall impact of POD.
Another risk factor for delirium after heart surgery is the use of CPB.6 Through oxidative stress and by activating proinflammatory and proapoptotic signalling pathways, CPB plays a crucial role in systemic inflammatory response syndrome and organ function, including the brain.24 An increase in inflammatory mediators may significantly contribute to the development of delirium by disrupting the blood–brain barrier integrity and causing brain cell oedema.23 25 During cardiac surgery, administering agents having antioxidant properties, either intravenously or in the cardioplegia solution, may help reduce reactive oxygen species and oxidative stress during CPB. Studies have demonstrated that mannitol can be effective in reducing oxidative stress through its antioxidant effects.26 There are several causes of delirium, including increased intracranial pressure. This can be a function of haemodilution from fluids that are used during heart surgery, such as the priming of CPB. Increased intracranial pressure can decrease cerebral perfusion pressure and cerebral blood flow, which can result in impaired consciousness and delirium.9 The use of mannitol during heart surgery with its hyperosmotic property can reduce the water content in the central area of oedema as well as intracranial pressure, further playing an effective role in reducing the incidence of delirium. The results of the current study highlight the effectiveness of mannitol infusion in reducing delirium. These findings are consistent with the research conducted by Hamiko et al who found that mannitol infusion is associated with a decreased incidence of POD, shorter mechanical ventilation time, reduced hospitalisation in GCU and ICU, as well as lower treatment costs.3 Claesson Lingehall et al also stated in their study that the use of mannitol as a hyperosmolar solution for priming of CPB does not increase the risk of delirium, which confirms the safety of mannitol and does not contradict the findings of our study.22
In our study, we found that the group receiving mannitol had a shorter time on mechanical ventilation, a shorter stay in ICU and a lower 30-day mortality rate in the hospital, although these differences were not statistically significant. It appears that gathering more evidence from studies with a larger number of participants is needed to determine the statistical significance. This is important because delirium is a contributing factor to mortality and prolonged hospitalisation after surgery in the ICU and reducing delirium could lead to a decrease in these complications. Both our study and previous research suggest that using mannitol during CPB could help prevent POD. Various limitations affected this study, but we addressed them by randomising and blinding the study. The single-centred nature of the study is another drawback. A type II error may be present.
Conclusion
In conclusion, the present study showed that adding mannitol to the prime for CPB did not have an impact on ventilation time, length of stay in the ICU or 30-day mortality. However, the incidence of delirium decreased in patients who were given mannitol. This indicates that using mannitol in CPB prime could be an effective method for decreasing delirium following heart surgery.
Supplemental material
Data availability statement
Data are available on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Urmia University of Medical Sciences (Ethics Committee) IR.UMSU.REC.1401.319. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
This study was conducted as part of a master's thesis financially supported by Urmia University of Medical Sciences. The authors would like to express their gratitude to the cardiac surgery team at Shahid Madani Heart Center, as well as the cardiovascular, medical and research centres.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors AF is responsible for the overall content as guarantor. All authors took full responsibility for the conception, study direction, data collection, analysis, interpretation and manuscript submission. All authors contributed to the work’s conception, design and acquisition. MHM, AF and EB: conceptualisation, methodology and writing–original draft preparation. AK, SN, EB and AF: supervision, investigation and writing–original draft preparation. VA: conducted the statistical analysis and interpretation.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.