Keywords
aortic valve - postoperative care - intensive care - outcomes
Introduction
Postoperative delirium (POD) is a common neurological complication after surgery,
most often seen in elderly patients. Besides age, cardiac function, diabetes, vascular
disease, and pre-existent cognitive impairment, POD is also independently associated
with invasiveness and duration of cardiac surgery.[1] In this regard, patients undergoing cardiopulmonary bypass (CPB) seem to be vulnerable
for the development of POD, which is diagnosed in ≈30 to 52% in this population.[2]
[3] Most notably, POD is associated with longer intensive care unit (ICU) and hospital
stay, long-term cognitive impairment, and increased mortality,[4]
[5]
[6] consequently leading to increase in treatment expenses.[7]
[8] Therefore, attempts to reduce POD in these patients are important.
It has been reported that CPB itself can promote the development of POD.[9] Preparation of the CBP is not uniform: hypo-oncotic priming solutions of the heart–lung
machine (HLM) can result in interstitial fluid retention and lead to cerebral edema;
the latter has been shown to promote encephalopathy and delirium, but the underlying
mechanism remains unclear.[10] In contrast, an increased oncotic pressure is beneficial for maintaining a sufficient
mean arterial pressure (MAP) and has been shown to improve organ perfusion.[11] As a consequence, colloids such as human albumin (HA) or hydroxyethyl starch (HES)
are often added to the priming solution of the HLM.[12]
[13] However, a clear advantage for using colloidal solutions could not be demonstrated.[12]
[14] Moreover, studies report that the use of HES and HA are associated with renal failure,[15]
[16] even though conflicting data exist with respect to nephroprotective properties of
HA, showing reduced risk of acute renal failure after off-pump coronary artery bypass
surgery.[17] Most importantly, HES administration was related to early POD development.[18]
Mannitol is commonly used to reduce intracranial pressure and edema due to its osmodiuretic
effects[19] and may be added to the priming solution during CBP to maintain higher oncotic pressure.[20] But so far, no study has examined an association between mannitol application during
CBP and POD. Therefore, this study aimed to examine the effect of mannitol supplementation
during CBP on the development of POD and other parameters of postoperative outcome
in a homogenous cohort of patients undergoing elective surgical aortic valve replacement
(AVR).
Materials and Methods
Patient Selection and Group Definition
This retrospective single-center study was performed on 259 patients, who were admitted
for first time elective surgical AVR between 2014 and 2017. Indications for AVR were
aortic stenosis, aortic regurgitation, or elective AVR. All patients undergoing concomitant
heart surgeries (e.g., coronary artery bypass graft surgery, other valve procedures,
etc.) or David/Bentall procedures were excluded from the study. One patient was diagnosed
with aortic valve endocarditis, but this was not associated with enhanced inflammatory
parameters and only diagnosed in echocardiography. In all patients included in our
study, retrograde autologous priming (RAP) of the HLM was performed. All patients
receiving albumin or crystalloid priming were excluded from this study. A comprehensive
dataset of pre-, intra-, and postoperative parameters was generated by review of patient
charts and IT-based datasets. Information on preoperative baseline characteristic,
risk factors, and comorbidities, such as renal (need for hemodialysis) or liver failure,
were recorded. Also, we screened all available preoperative patient's data (recent
medical reports, information provided by the patients and/or family members) with
respect to cerebrovascular insults, neurological and cognitive impairment (e.g., preexisting
dementia, Alzheimer's and Parkinson's disease, epilepsy), psychiatric or mental disorders
(e.g., schizophrenia, depression), daily medication, and drug or alcohol abuse.
Within the aforementioned period of time, all patients, except those with complicated
preoperative course, for example, organ failure, preoperative catecholamine therapy,
the need for mechanical circulatory support (MCS), or the above-described psychic
or mental disorders and drug or alcohol abuse, were included in this study. The preoperative
risk score European System for Cardiac Operative Risk Evaluation II (EuroSCORE II)
was calculated for each patient. All patients who were eligible for this retrospective
study were divided into two groups: 188 patients having received mannitol during CBP
(mannitol group) and 71 patients having not received (nonmannitol group).
Surgical Procedure and Mannitol Administration
All patients were classified as American Society of Anesthesiologists III and IV,
and a standard anesthetic protocol was performed using sufentanil, etomidate, and
rocuronium for induction of anesthesia followed by endotracheal intubation. Anesthesia
was maintained using sufentanil and sevoflurane. Standard monitoring comprised peripheral
oxygen saturation, electrocardiogram, temperature, and invasive arterial blood pressure.
Furthermore, a trilumen central venous catheter, a high-flow sheath introducer, as
well as a urinary catheter was placed. During CBP, sevoflurane was administered continuously
during CBP. Surgical procedure was similar in all patients: complete median or superior
median ministernotomy was performed. To achieve an activating clotting time of >450 seconds,
anticoagulation with 400 to 500 U/kg sodium heparin was initiated. After cannulation
of the ascending aorta and the right atrium, CBP was established using a Terumo Advanced
Perfusion System 1 (Terumo Cardiovascular Systems, Ann Arbor, Michigan, United States).
The extracorporeal circuit included a venous hardshell cardiotomy reservoir (Maquet,
Wayne, New Jersey, United States), a roller pump system, and a membrane oxygenator
(Quadrox oxygenator, Maquet) equipped with a heat exchanger and an arterial filter
system. The nonheparin-coated tube system was primed with crystalloid solution (≈1,000 mL
Jonosteril, Fresenius, Bad Homburg, Germany) and 10,000 U of heparin. In all patients,
RAP was performed after connecting the HLM to the introduced cannulas.
In this study, 188 patients were treated with 0.5 g/kg body weight mannitol solution
(Osmosteril 20%, Fresenius-Kabi GmbH, Bad Homburg, Germany) during extracorporeal
circulation (ECC) according to intraoperative diuresis and fluid intake: If intraoperative
diuresis was less than 50 mL/h after aortic unclamping and/or more than 3,000 mL crystalloid
solution were infused during ECC, mannitol was administered as bolus into the HLM
to augment diuresis and to minimize fluid movement to the extravascular space. All
other patients did not receive mannitol. The mannitol dosage was in accordance with
other studies.[21]
[22] Mannitol was not part of the priming solution, as no effects of mannitol on osmolarity
of the priming solution have been observed in patients with normal cardiac and renal
function.[21] Cardioprotection and myocardial arrest were achieved using Bretschneider HTK-cardioplegia
(Custadiol, Dr. Franz Kohler Chemie GmbH, Bensheim, Germany). A nonpulsatile pump
flow of 2.2 to 2.6 L/min/m2 was conducted to maintain a MAP of 50 to 60 mm Hg during CBP.
Postoperative Care
After the surgical procedure, all patients were transferred to the ICU, where sedation
was achieved using propofol and sufentanil. Airway pressure release ventilation was
performed, with an inspiratory:expiratory ratio of ≈1.5:2 seconds, corresponding to
a respiratory rate of ≈17 breaths/min. Tidal volume of 6 to 8 mL/kg was used, and
positive inspiratory pressure was set to 20 cm H2O, while positive end-expiratory pressure of 10 cm H2O was applied. The fraction of insufflated oxygen was adjusted according to arterial
blood gas analysis. Early extubation and transfer to the intermediate care ward were
attempted in all cases. Further analgesic regimen followed piritramide bolus injection
(3–5 mg intravenous).
Duration of surgery, CBP and aortic cross-clamping time, parameters of organ function,
and other routine laboratory variables were recorded. Outcome data further included:
ventilator-associated pneumonia, need for reintubation, renal failure with need for
continuous venovenous hemofiltration or -dialysis (CVVH/HD, length of ICU and hospital
stay, nurse workload score (“Therapeutic Intervention Scoring System” [TISS]-10),
and monitoring of the “Simplified Acute Physiology Score II” (SAPS II), as well as
30-day mortality and the total hospital treatment costs.
Assessment of Postoperative Delirium
For assessment of POD, criteria of the Diagnostic and Statistical Manual of Mental
Disease, Fifth Edition were applied.[23] Delirium is characterized by fluctuating clinical course, for example, memory deficit,
disorientation, language, visuospatial ability, or perception disorders. The development
of delirium within short time was assessed daily during ICU stay using the confusion
assessment method for the intensive care unit (CAM-ICU) flowsheet.[24] Patients with sedation (“Richmond Agitation and Sedation Scale” score < −3), stroke
symptoms, or nonnative German speakers were excluded from the study. Patients with
a positive CAM-ICU test were defined as POD positive.
Statistical Analysis
Data are presented as means with standard deviation. Continuous variables were tested
using either the Student's t-test, or, in the case of a nonnormal distribution (D'Agostino's K-squared test),
the Mann–Whitney's U test, if two groups were compared at one time point. Linear mixed models were used
to investigate differences between mannitol and nonmannitol groups on the time course
of various parameters of interest measures (lactate, serum creatinine, and bilirubin).
Categorical data were expressed as percentages and tested using the Pearson's chi-square
test. A p-value of <0.05 was considered statistically significant.
Univariable and multivariable logistic regression were employed to investigate risk
factors for POD. The following risk factors were investigated: Patients age, diabetes
mellitus, white blood cell (WBC) at admission, preoperative sodium, creatinine, hemoglobin
and hematocrit values, EuroScore II, aortic cross-clamping time, CBP time, reperfusion
time, minimum and mean sodium concentrations during CBP, minimum intraoperative hemoglobin,
minimum intraoperative arterial oxygen saturation, minimum intraoperative MAP, mannitol
substitution during CBP, amount of cardioplegic solution, fluid balance after CBP,
amount of blood products transfusion during surgery, total diuresis during CBP, perioperative
ventilation time, need for postoperative reintubation, need for postoperative CVVH/HD
or dialysis, pneumonia, SAPS II score 24 hours after ICU admission, postoperative
maximum creatinine, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase
(AST), and MAP 1 hour after surgery.
IBM SPSS statistics (SPSS Inc., Chicago, Illinois, United States, version 25) and
R (version 3.6.2, R Core Team [2018]. R: A language and environment for statistical
computing. R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/) were used for statistical analysis.
Results
No significant differences in terms of demographic and preoperative baseline characteristics
were observed between the two groups: Most importantly, no differences were seen in
pre- and postoperative serum creatinine, bilirubin, and ALT/AST levels ([Table 1] and [Supplementary Table S1] [online only]), indicating no differences in renal and liver function in both groups.
The pre- and postoperative lactate levels as parameter for an anaerobic metabolism
and thus surrogate parameter of reduced organ perfusion did not show any significant
difference between the groups. Also, the hemoglobin concentration, WBC, and platelet
count before and after surgery were not different ([Table 1] and [Supplementary Table S1] [online only]).
Table 1
Preoperative patients' characteristics
|
Total (n = 259)
|
Mannitol (n = 188)
|
Nonmannitol (n = 71)
|
p-Value
|
|
Age (y)
|
66.6 ± 10.2
|
66.0 ± 10.8
|
67.9 ± 8.1
|
0.182
|
|
Female
|
88 (34.0%)
|
64 (34.0%)
|
24 (33.8%)
|
0.971
|
|
Height (m)
|
1.74 ± 0.3
|
1.72 ± 0.1
|
1.80 ± 0.7
|
0.126
|
|
Weight (kg)
|
82.7 ± 15.2
|
82.4 ± 15.1
|
83.5 ± 15.5
|
0.603
|
|
BMI (kg/m2)
|
28.2 ± 9.2
|
27.8 ± 4.8
|
29.3 ± 15.8
|
0.248
|
|
EuroSCORE II
|
1.83 ± 0.75
|
1.80 ± 0.69
|
1.92 ± 0.90
|
0.207
|
|
Diabetes mellitus
|
56/253 (22.1%)
|
39/183 (21.3%)
|
17 (24.3%)
|
0.610
|
|
Hemoglobin (g/dL)
|
13.4 ± 1.9
|
13.5 ± 1.8
|
13.3 ± 1.9
|
0.502
|
|
WBC (g/L)
|
7.6 ± 2.5
|
7.7 ± 2.5
|
7.4 ± 2.5
|
0.490
|
|
Creatinine (mg/dL)
|
1.1 ± 0.6
|
1.0 ± 0.4
|
1.1 ± 0.9
|
0.341
|
|
Bilirubin (mg/dL)
|
0.7 ± 0.6
|
0.7 ± 0.7
|
0.6 ± 0.4
|
0.435
|
|
ALT (U/L)
|
31.0 ± 15.6
|
31.5 ± 15.1
|
29.1 ± 17.1
|
0.455
|
|
AST (U/L)
|
26.7 ± 17.3
|
27.1 ± 18.9
|
25.3 ± 11.2
|
0.508
|
|
Left ventricular ejection fraction
|
|
> 50%
|
218 (84.1%)
|
154 (81.9%)
|
64 (90.1%)
|
0.296
|
|
30–50%
|
35 (13.5%)
|
29 (15.4%)
|
6 (8.5%)
|
|
< 30%
|
6 (2.3%)
|
5 (2.7%)
|
1 (1.4%)
|
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI,
body mass index; EuroSCORE II, European System for Cardiac Operative Risk Evaluation
II; Mannitol, patients received mannitol during extracorporeal circulation; Nonmannitol,
patients without mannitol treatment; WBC, white blood cell.
Notes: Summary of preoperative patients' characteristics. Values are expressed as
mean ± standard deviation, or as number and percentage (in bracket). Significant changes
are displayed in italics.
[Table 2] summarizes intraoperative data, sowing no differences with respect to duration of
surgery, aortic cross-clamping time and CBP time, MAP, and amount of cardioplegic
solution. Fluid balance during CBP was significantly less positive in mannitol compared
with the nonmannitol patients, being associated with higher diuresis and filtered
fluid amount in the same group. No difference was observed with respect to intraoperatively
transfused red blood cell concentrates. Beside hemoglobin and lactate concentration,
minimum and mean serum sodium concentrations during CBP were similar in both groups,
going along with comparable postoperative diuresis and total fluid balance after 24 hours
([Supplementary Table S1] [online only]).
Table 2
Intraoperative data
|
Total (n = 259)
|
Mannitol (n = 188)
|
Nonmannitol (n = 71)
|
p-Value
|
|
Time to skin closure (min)
|
230.6 ± 58.7
|
232.0 ± 59.2
|
226.8 ± 57.7
|
0.284
|
|
CBP time (min)
|
120.8 ± 111.4
|
115.0 ± 29.4
|
112.5 ± 24.5
|
0.695
|
|
Aortic clamp time (min)
|
86.8 ± 41.0
|
85.2 ± 21.3
|
82.7 ± 18.8
|
0.607
|
|
Cardioplegic solution (mL)
|
1,776.8 ± 354.9
|
1,792.2 ± 384.6
|
1,735.9 ± 258.3
|
0.671
|
|
Fluid balance on CBP (mL)
|
223.5 ± 1,240.5
|
132.5 ± 21.3
|
464.6 ± 922.7
|
0.006
|
|
Filtered fluid volume (mL)
|
2,126.7 ± 1,282.4
|
2,165.3 ± 1,161.3
|
2,024.6 ± 1,563.5
|
0.046
|
|
Diuresis during CBP (mL)
|
369.8 ± 339.0
|
386.3 ± 326.0
|
326.3 ± 370.1
|
0.022
|
|
MAP
|
|
Minimum (mm Hg)
|
54.6 ± 8.6
|
54.4 ± 9.0
|
55.1 ± 7.6
|
0.578
|
|
Maximum (mm Hg)
|
67.0 ± 9.1
|
66.6 ± 9.3
|
68.0 ± 8.3
|
0.098
|
|
Hemoglobin concentration
|
|
Minimum (g/dL)
|
9.58 ± 1.61
|
9.54 ± 1.63
|
9.70 ± 1.55
|
0.523
|
|
Maximum (g/dL)
|
11.11 ± 1.40
|
11.14 ± 1.43
|
11.05 ± 1.30
|
0.981
|
|
Serum sodium during CBP
|
|
Mean (mmol/L)
|
132.40 ± 3.90
|
132.29 ± 3.83
|
128.18 ± 6.07
|
0.480
|
|
Minimum (mmol/L)
|
128.54 ± 5.86
|
132.69 ± 4.09
|
129.51 ± 5.19
|
0.080
|
|
RCC (units)
|
0.35 ± 0.77
|
0.32 ± 0.71
|
0.42 ± 0.90
|
0.625
|
|
Maximum lactate (mmol/L)
|
1.53 ± 1.89
|
1.60 ± 2.20
|
1.35 ± 0.51
|
0.444
|
Abbreviations: CBP, cardiopulmonary bypass; MAP, mean arterial pressure; Mannitol,
patients received mannitol during extracorporeal circulation, Nonmannitol, patients
without mannitol treatment; RCC, red blood cell concentrate.
Notes: Summary of surgery-related intraoperative variables. Values are expressed as
mean ± standard deviation. Significant changes are displayed in italics.
Further, data on postoperative outcome and adverse events are displayed in [Table 3] and [Supplementary Table S1] (online only): no difference was seen with respect to use of MCS, need for cardiopulmonary
resuscitation, incidence of pneumonia, number of postoperative myocardial infarction,
atrioventricular block higher than second degree, need for pacemaker implantation,
CVVH/D, and rethoracotomy. However, most importantly, the incidence of POD was significantly
higher in the nonmannitol compared with the mannitol group. Furthermore, absence of
mannitol was associated with longer ventilation time, higher reintubation rate, increased
ICU readmission rates, and a prolonged ICU and total hospital stay. Accordingly, total
treatment expenses were ≈2,700 € higher in nonmannitol patients. Also, absence of
mannitol treatment was associated with significantly higher mortality-predicting SAPS
II score 24 hours after surgery. In [Table 4], data were examined according to the criterion “delirium”: Here, the above-mentioned
findings on postoperative outcome are accredited, while TISS-10 score and associated
treatment expenses (≈5,000 € higher costs during hospital stay) were significantly
higher in patients suffering from POD.
Table 3
Postoperative outcome
|
Total (n = 259)
|
Mannitol (n = 188)
|
Nonmannitol (n = 71)
|
p-Value
|
|
POD, n (%)
|
50 (19.3%)
|
26 (13.8%)
|
24 (33.8%)
|
0.001
|
|
Reintubation
|
13 (5.1%)
|
5 (2.7%)
|
8 (11.3%)
|
0.009
|
|
SAPS II score 24 h
|
29.7 ± 7.2
|
28.7 ± 7.1
|
32.2 ± 7.0
|
<0.001
|
|
Ventilation time (h)
|
19.0 ± 33.9
|
17.1 ± 33.1
|
24.1 ± 35.6
|
0.021
|
|
ICU stay (h)
|
81.5 ± 147.3
|
70.0 ± 110.2
|
112.0 ± 214.7
|
0.040
|
|
Readmission to ICU
|
18 (6.9%)
|
9 (4.8%)
|
9 (12.7%)
|
0.026
|
|
In-hospital stay postop (d)
|
14.5 ± 12.8
|
12.6 ± 9.7
|
17.8 ± 11.3
|
<0.001
|
|
Treatment expenses (€)
|
17,351 ± 5,168
|
16,606 ± 3,842
|
19,349 ± 7,341
|
<0.001
|
|
30-d mortality
|
7 (2.7%)
|
7 (3.7%)
|
0 (0.0%)
|
0.099
|
Abbreviations: ICU, intensive care unit; Mannitol, patients received mannitol during
extracorporeal circulation; Nonmannitol, patients without mannitol treatment; POD,
postoperative delirium; postop, postoperative; SAPS II, Simplified Acute Physiology
Score II.
Notes: Summary of data on postoperative outcome and adverse events. Values are expressed
as mean ± standard deviation, or as number and percentage (in bracket). Significant
changes are displayed in italics.
Table 4
Comparison between delirious and nondelirious patients
|
Delirium (n = 50)
|
Nondelirium (n = 209)
|
p-Value
|
|
Pneumonia
|
14 (28.0%)
|
7 (3.3%)
|
<0.001
|
|
Reintubation
|
11 (22.0%)
|
2 (1.0%)
|
<0.001
|
|
SAPS II score 24 h
|
35.0 ± 7.3
|
28.4 ± 6.7
|
<0.001
|
|
TISS-10 24 h
|
24.6 ± 4.6
|
19.3 ± 6.8
|
<0.001
|
|
Ventilation time (h)
|
31.6 ± 39.4
|
16.0 ± 31.8
|
<0.001
|
|
ICU stay in h
|
193.6 ± 234.9
|
54.6 ± 100.5
|
<0.001
|
|
Readmission to ICU
|
15 (30.0%)
|
3 (1.4%)
|
<0.001
|
|
In-hospital stay postop (d)
|
20.2 ± 18.9
|
18.4 ± 76.4
|
0.003
|
|
Treatment expenses (€)
|
21,625 ± 8,733
|
16,326 ± 3,113
|
<0.001
|
|
30-d mortality
|
1 (2.0%)
|
6 (2.9%)
|
0.116
|
Abbreviations: ICU, intensive care unit; postop, postoperative; SAPS II, Simplified
Acute Physiology Score II; TISS, Therapeutic Intervention Scoring System.
Notes: Summary of data on postoperative outcome and adverse events compared between
delirious and nondelirious patients. Values are expressed as mean ± standard deviation,
or as number and percentage (in bracket). Significant changes are displayed in italics.
In multivariable regression analysis, mannitol was an independent and statistically
significant factor associated with lower incidence of POD ([Table 5]). A visualization of this model using prototypical values is shown in [Fig. 1]. A receiver operating characteristics analysis was performed to investigate the
discrimination ability of our model. Our model showed an area under the curve of 0.84
([Fig. 2]; 95% confidence interval: 0.78–0.91; p < 0.001). Recursive partitioning was utilized to investigate and visualize the influence
of mannitol on POD and is displayed in [Fig. 3].
Table 5
Multivariable logistic regression model
|
Factor
|
OR
|
95% CI
|
p-Value
|
|
Intercept
|
0.0061
|
0.0008–0.0383
|
<0.001
|
|
Mannitol substitution
|
0.4025
|
0.1815–0.8930
|
0.02
|
|
Reintubation
|
9.0824
|
1.9884–65.2400
|
0.009
|
|
Pneumonia
|
5.0479
|
1.4688–17.7855
|
0.009
|
|
SAPS II score 24 h
|
1.0962
|
1.0381–1.1620
|
0.001
|
|
EuroSCORE II
|
1.6755
|
1.0754–2.6725
|
0.03
|
Abbreviations: CI, confidence interval; EuroSCORE II, European System for Cardiac
Operative Risk Evaluation II; OR, odds ratio; SAPS II, Simplified Acute Physiology
Score II.
Notes: Results of the multivariate logistic regression analysis. Significant changes
are displayed in italics.
Fig. 1 A visualization of our multivariable model ([Table 5]) using prototypical values for reintubation, EuroSCORE II, mannitol substitution
and SAPS II score. EuroSCORE II, European System for Cardiac Operative Risk Evaluation
II; ICU, intensive care unit; POD, postoperative delirium; SAPS II, Simplified Acute
Physiology Score II.
Fig. 2 ROC analysis for delirium and mannitol substitution. The ROC curve and the AUC show
a good discrimination ability of our multivariable model (AUC: 0.84; 95% CI: 0.78–0.91;
p < 0.001). AUC, area under the curve; CI, confidence interval; ROC, receiver operating
characteristic.
Fig. 3 Recursive partitioning and conditional inference trees. An analysis with recursive
partitioning and conditional inference trees showing the influence of mannitol on
POD in all EuroSCORE II groups. EuroSCORE II, European System for Cardiac Operative
Risk Evaluation II; POD, postoperative delirium.
Discussion
In this study, we were able to show that mannitol administration during ECC decreases
the incidence of POD in patients undergoing AVR. POD is a severe postoperative neurological
complication being associated with increased morbidity and mortality, longer hospital
stays, and enhanced medical costs.[25]
[26]
[27] Accordingly, we show that nurse workload index TISS-10, mortality predicting SAPS
II,[28]
[29] duration of mechanical ventilation, duration of ICU and hospital stays, readmission
to ICU, and incidence for pneumonia were significantly higher in patients suffering
from POD after AVR. Further, POD was associated with significantly enhanced medical
costs, which has also been reported after major urological surgery.[27] POD, particularly its hypoactive form, is often overlooked during ICU, which could
be associated with far-reaching consequences.[30] We applied the CAM-ICU test that has been proven to be suitable for POD screening
of postcardiotomy patients.[24] In this regard, early recognition and treatment of POD have been demonstrated to
be key for the reduction, duration, and severity of POD with associated negative outcomes.[31]
Various studies have investigated predisposing and precipitating factors of POD in
postcardiotomy patients.[32]
[33] Beside individual patient conditions, procedure-associated factors, such as the
complexity of surgery, and consequently, duration of ECC have been identified as independent
predisposing factors for postcardiotomy POD.[34]
[35] Also, besides their association with postoperative renal failure, the use of HES
and HA as HLM priming solutions is related to early POD.[18] Although RAP is the standard procedure in many hospitals, the HLM tubing system
is primed with crystalloid solution, potentially resulting in a drop in oncotic pressure.
With respect to the kidney-related disadvantages of HES, mannitol has been used during
ECC for years to maintain an elevated oncotic pressure and a more stable MAP.
While most studies have focused on the effect of mannitol on postoperative renal failure,[36]
[37] we investigated the impact of mannitol substitution on POD and postoperative outcome
in a cohort of postcardiotomy patients undergoing elective AVR. Patients with preexisting
mental conditions were excluded. Our data reveal no differences with respect to preoperative
demographic characteristics, organ function, coagulation, and inflammation parameters
between the mannitol and the nonmannitol groups. Also, EuroSCORE II was not different.
Most importantly, we show in multivariable regression analysis that mannitol was an
independent and statistically significant factor associated with lower incidence of
POD; while POD incidence in nonmannitol patients was in accordance with other studies,[3]
[33] mannitol supplementation was associated with only 13.8% POD in patients with a comparable
ECC and aortic cross-clamping time. A visualization of our model showed significantly
lower probability of POD independent of the operative risk stratification of the patient
(EuroSCORE II), need for reintubation, development of pneumonia, or SAPS II 24 hours
score. Recursive partitioning was utilized to visualize the influence of mannitol
on POD, showing that with increasing EuroSCORE II, mannitol treatment is associated
with lower incidence of POD. Furthermore, lower incidence of POD in the mannitol group
was accompanied by shorter ventilation time, ICU and total hospital stay, lower ICU
readmission rate, and reintubation rate and lower SAPS II score. The 30-day mortality
was not affected.
Against the background of increasing shortage of health care professionals, identification
and elimination of modifiable risk factors and potentially preventing POD in postcardiotomy
patients have a high priority. From the economic perspective, longer ventilation time
with prolonged ICU stay causes increased treatment expenses.[5]
[7]
[26] Our data are in line with previous studies, connecting POD to longer hospitalization
time and higher treatment expenses after major surgeries.[7]
[27] Moreover, we could show that mannitol substitution was associated with significantly
reduced treatment costs. Therefore, our data suggest that patients with no mannitol
treatment have a higher probability for development of POD, causing higher need for
ICU stay, which in return leads to lower number of surgeries. Besides higher treatment
expenses, this potentially contributes to lower earnings of the surgical department.
In the past, effects of mannitol administration during cardiac surgery have been studied
focusing on postoperative acute renal failure, showing that mannitol has no effect
on renal function during cardiac surgery in patients with or without established renal
dysfunction.[36]
[37] In agreement with this, we did not observe signs of renal failure after mannitol
administration, as demonstrated by comparable postoperative maximum serum creatinine
values, accompanied by comparable total diuresis and fluid balance after 24 hours
in both groups. Also, the trend of serum creatinine as well as the need for CVVH has
been similar between the two groups. These data are in line with the above-cited studies
showing neither advantage nor disadvantage of mannitol substitution on renal function;
also, the effect of mannitol removal from the priming solution based on observations
of high volume and potassium requirements resulting from excessive diuresis did not
have any effect on electrolytes, fluid status, and other outcomes in another study.[38]
Furthermore, a potential role of the sodium shift induced by Bretschneider solution
for induction of POD by inducing an acute hyponatremia has to be considered, as Aldemir
et al reported that hyponatremia is a predicting factor for delirium in a surgical
ICU.[39] In this regard, univariable and multivariable logistic regression showed that both
mean and minimum serum sodium concentration during CBP were not independently associated
with incidence of POD in our study. This suggests that the use of hyponatremic Bretschneider
cardioplegic solution has no impact on prevalence of POD.
With respect to possible underlying mechanisms, it is known that CBP promotes systemic
inflammatory response syndrome due to activation of the complement system, resulting
in a reaction including cytokines release, leukocyte activation, and ROS generation.[40] This cascade leads to endothelial dysfunction leading to interstitial edema. This
may disrupt the blood–brain barrier and result in neuroinflammation with activation
of microglial cells.[41] Neuroinflammation itself leads to fluid accumulation and swelling, favoring POD.[42] Here, this mechanistic concept of mannitol use to reduce cell edema could be transferred
to cardiac surgery. Further, it has been shown that mannitol reduces the plasma levels
of ROS,[43] and reportedly, antioxidant therapy with mannitol during CBP induced immunosuppression
after coronary artery bypass graft surgery.[22] In this light, mannitol might also exert its antidelirious effect via suppression
of neuroinflammation. But an examination of the underlying mechanisms of mannitol
treatment and its connection to POD were beyond the scope of this study.
In summary, our data suggest that mannitol supplementation should be considered in
patients undergoing CBP. However, the appropriate dosage should be accredited in patients
with impaired renal function.
Limitation of the Study
Our study is limited due to its retrospective character, resulting in unequally sized
patient groups. An additional limitation of the study is the lack of preoperative
cognitive assessment and evaluation of preoperative delirium using common confusion
assessment methods such as the Montreal Confusion Assessment or Mini-Mental Test.
In addition, we do not provide data on postoperative quality of life. Regarding the
use of Bretschneider cardioplegic solution and associated intraoperative hyponatremia
during CBP, we acknowledge that the beneficial effects of mannitol may not be observed
in patients treated with modern blood cardioplegia solutions (e.g., Buckberg, Calafiore,
etc.). Therefore, any conclusions will need to be proven by a randomized controlled
trial.
Conclusion
Early recognition of POD is important since it is associated with worse postoperative
outcome, prolonged ICU and hospital stay, and thus higher treatment expenses. Our
study shows for the first time that supplementation with mannitol during ECC is associated
with lower incidence of POD in elective AVR. The 30-day mortality and other serious
postoperative complications, especially renal failure, were comparable. Considering
mannitol use during CBP could lead to less POD and might result in significant cost
savings.
