Hamed, A., Elwakil, R., Gawish, E., Kamel, W., Elbaz, A. (2023). Sub-Clinical Hepatic Encephalopathy in Cirrhotic Patients Subjected to Sedation with either Propofol or Midazolam. Afro-Egyptian Journal of Infectious and Endemic Diseases, 13(3), 190-196. doi: 10.21608/aeji.2023.219593.1298
Amr Hamed; Reda Elwakil; Eman Gawish; Walid Y. Kamel; Ahmed Elbaz. "Sub-Clinical Hepatic Encephalopathy in Cirrhotic Patients Subjected to Sedation with either Propofol or Midazolam". Afro-Egyptian Journal of Infectious and Endemic Diseases, 13, 3, 2023, 190-196. doi: 10.21608/aeji.2023.219593.1298
Hamed, A., Elwakil, R., Gawish, E., Kamel, W., Elbaz, A. (2023). 'Sub-Clinical Hepatic Encephalopathy in Cirrhotic Patients Subjected to Sedation with either Propofol or Midazolam', Afro-Egyptian Journal of Infectious and Endemic Diseases, 13(3), pp. 190-196. doi: 10.21608/aeji.2023.219593.1298
Hamed, A., Elwakil, R., Gawish, E., Kamel, W., Elbaz, A. Sub-Clinical Hepatic Encephalopathy in Cirrhotic Patients Subjected to Sedation with either Propofol or Midazolam. Afro-Egyptian Journal of Infectious and Endemic Diseases, 2023; 13(3): 190-196. doi: 10.21608/aeji.2023.219593.1298
Sub-Clinical Hepatic Encephalopathy in Cirrhotic Patients Subjected to Sedation with either Propofol or Midazolam
1Department of Tropical Medicine, Ain Shams University, Abbasiya, Cairo, Egypt
2Department of Anesthesia, Intensive Care and Pain Management, Ain Shams University, Abbasiya, Cairo, Egypt
Abstract
Background and study aim: Patients with hepatic impairment are at higher risk for sedation complications. The aim of this study is to determine the impact of propofol in comparison to midazolam on the occurrence of sub-clinical hepatic encephalopathy in liver cirrhotic patients undergoing upper gastrointestinal endoscopy (UGE). Patients and Methods: The study population involved 70 patients. Group A included 10 non-hepatic patients who underwent UGE without sedation. Group B included 30 patients with CLD received midazolam. Group C included 30 patients with CLD received propofol. The level of encephalopathy was determined by number connection test (NCT). Results: In group B there was mild decrease in systolic blood pressure during and after than before UGE with compensatory tachycardia. Also, there was some decrease in oxygen saturation during UGE (>90%) which resolved after oxygen flow. Patients of group C showed decrease in systolic blood pressure at onset of injection of propofol with mild tachycardia. There was mild decrease in oxygen saturation during procedure more significant than what happened in midazolam group with no need for intubation. Regarding NCT one hour after and delta change of NCT, they showed significant increase in group B versus group C. Times of procedure and recovery were significantly prolonged in group B in comparison to group C. Conclusion: Midazolam exacerbates sub-clinical encephalopathy. The hypotension and tachycardia during the procedure were more significant in midazolam group than propofol group. Subjects receiving propofol showed shorter induction, time of procedure and recovery periods .
Highlights
Midazolam exacerbates sub-clinical encephalopathy and produce hypotension and tachycardia during upper gastrointestinal endoscopy procedure more than propofol.
Propofol showed shorter induction, time of procedure and recovery periods during upper gastrointestinal endoscopy.
Hepatic encephalopathy is an acute or chronic neurological disorder due to liver disease [1]. Sub-clinical hepatic encephalopathy or minimal hepatic encephalopathy (MHE), shows measurable neuropsychological disorders, but with normal neurological and mental status on clinical examination [2, 3].
Upper gastrointestinal endoscopy (UGE) is needed to be done regularly in chronic liver disease (CLD) patients for management and follow-up of esophageal varices, gastric varices and portal hypertensive gastropathy which are complications due to portal hypertension [4]. Sedation is needed during this procedure to help patient’s tolerance [5].
Patients with CLD are in risk of sedation complications during UGE. This is attributed to metabolization of some of these sedative drugs in the liver, as well as due to the possible hemodynamic changes that are associated with the anesthetic drugs, due to higher plasma level and prolonged effect of these drugs due to their delayed clearance [6].
Midazolam is a benzodiazepine that is frequently used for mild sedation in the general population undergoing UGE [7]. It is anxiolytic and amnesic with half-life
Propofol is a short-acting anesthetic drug that can be used drug during UGE. In comparison to benzodiazepines, it has convenient pharmacokinetic properties [10].
The aim of this study is to determine the impact of propofol in comparison to midazolam on the occurrence of sub-clinical hepatic encephalopathy in liver cirrhotic patients undergoing UGE.
PATIENTS AND METHODS
Study population
We conducted retrospective observational study, comprised data of 70 Egyptian patients; male and female (aged 17 to 65years) collected from endoscopy center of Ain Shams University Hospital, Cairo, Egypt, from December 2014; 60 patients were hepatic patients with CLD regardless of etiology (Child-Pugh class A, B or C) and 10 patients non hepatic who underwent diagnostic or therapeutic UGE.
Inclusion criteria
All patients were matched for gender, age, body mass index (BMI) and divided to three groups. Group A included 10 control non hepatic patients who underwent UGE without sedation (neither propofol nor midazolam) for medical condition other than liver diseases. Group B included 30 patients with CLD received midazolam for sedation. Group C included 30 patients with CLD received propofol for sedation.
All patients were subjected to complete blood count, liver and renal profile investigations, number connection test before and after the procedure, estimation of time to recovery and time of the procedure and hemodynamic parameters (blood pressure, pulse, respiratory rate, and oxygen saturation) before, during and after sedation.
Exclusion criteria
Patients with psychiatric disease, active neurological disease, overt hepatic encephalopathy, alcohol or drug abuse, active respiratory illness, gastrointestinal hemorrhage, hepatocellular carcinoma and allergy to sedative drugs were excluded from the study.
Technique
The number connection test (NCT) defines the time required to connect sequentially the randomly placed circles labeled from 1 to 25. The degree of encephalopathy was determined according to the time needed to complete the test (Table 1).
Table (1): The degree of minimal hepatic encephalopathy according to NCT.
The degree of encephalopathy
Time of NCT (seconds)
Grade 0 (none)
15-30
Grade 1+ (mild)
31-50
Grade 2+ (moderate)
51-80
Grade 3+ (severe)
81-120
Grade 4+ (coma)
>121
NCT: Number connection test
Baseline vital signs including oxygen saturation, non-invasive blood pressure monitoring and 5-leads electrocardiogram before, throughout and post-procedure were recorded.
Intravenous bolus injection of midazolam 1 mg was given with increasing doses every 2–3 minutes till satisfactory sedation achieved suitable for carrying out the procedure or reaching total dose of 3 mg. Propofol was started with 1 mg/kg by an anesthesiologist followed by 0.5 mg/kg upon demand every 3 minutes. The patients were sedated by the aforementioned doses aiming to reach a moderate level of sedation where the patient respond appropriately to verbal command with or without light tactile stimuli. Patients who did not tolerate or the depth of the sedation was increased or even general anesthesia was ensured were excluded from the study.
A record of complications was made for the following events: desaturation <92% on pulse oximetry, decrease of systolic blood pressure
The degree of alertness and the time for full recovery were recorded. The full recovery was determined by the time when the patients will be oriented to the time, place and persons and achieving Aldrete score> 8. Aldrete scoring system is a 5 points scale including, activity, respiration, circulation, consciousness and oxygen saturation. the patients are assessed on a scale of 0 (worst), 1 (modest) and 2 points in the best condition.
The hemodynamic data, the ability to start oral fluids, the ability to stand-up without assistance and pain free were checked. Any pain encountered were managed using 1 gm of paracetamol intravenously. Patients who received narcotics as 0.5 mg/kg pethidine, were excluded from the study [11].
All patients repeated NCT after one hour, before discharge from the endoscopy post-anesthesia care unit (PACU) to ensure elimination of hypoxemia and antegrade amnesia which could influence the judgment.
After acceptance of all these parameters, the endoscopist discussed the procedure results with the patient and his family members.
Statistical analysis
Statistical Package for Social Science (IBM SPSS) version 23 was used for data analysis. Qualitative data was represented by number and percentages. Parametric quantitative data were represented by mean and standard deviations. Non-parametric quantitative data represented by median and inter-quartile range (IQR). Chi-square test compared qualitative data between groups. One-way ANOVA compared parametric quantitative data between groups. Mann-Whitney test compared non-parametric quantitative data. Sensitivity, specificity, positive and negative predictive values were determined. A receiver operating characteristic (ROC) analysis was formed and the best cut-off value for outcome was determined. The confidence interval was 95% and the accepted margin of error was 5%. P-value was considered significant if it is < 0.05.
RESULTS
Regarding the demographic data of studied population, the median age with inter-quartile range (IQR) for the studied cases in group A was 46.5 (40.5 –57.5) years old, 48.5 (38.25 – 42.5) years old in group B and 50 (45 – 57) years old in group C. Six of them (60%) were male patients in group A, 24 (80%) in group B and 20 (67%) in group C. The mean value of BMI was 27.8±6 in group A, 27.7±5.4 in group B and 28.1±3.9 in group C.
The whole number of CLD in the studied population were 60 patients, 40 patients (66.67%) due to HCV, 5 patients (8.3%) due to HBV, 7 patients (11.67%) due to bilharziasis, 3 patients (5.0%) due to Budd-Chiari syndrome, 2 patients (3.3%) due to autoimmune hepatitis and 3 patients (5.0%) of unknown etiology.
The number of cirrhotic patients with abnormal pre-sedation NCT times in the midazolam group was 18 patients (60%), and this number was raised to 25 patients (83.3%) after one hour following sedation with midazolam (P<0.001). The number of cirrhotic patients with abnormal pre-sedation NCT times in the propofol group was 22 patients (73.3%), and this number did not change after one hour following sedation with propofol (P= 0.714).
Regarding NCT before, table (3) showed significant increase in group C versus group B, while both groups B and C showed significant increase versus group A.
Regarding NCT one hour after, table (3) showed significant increase in group B versus group C, while both groups B and C showed significant increase versus group A.
Regarding delta change of NCT, table (3) showed significant increase in group B versus both groups A and C.
Table (3) showed significant higher NCT value one hour after than NCT before in group B (P<0.001).
Times of procedure and recovery was significantly increased in group B in comparison to group C [median (IQR): 15 (9.25-20) and 39 (38-40.25) respectively, p<0.001).
A significant decrease of blood pressure associated with significant increase in pulse and decrease of oxygen saturation was recorded during procedure in group B (P<0.001) and C (P<0.004). These changes were improved significantly after procedure except blood pressure in group B (P<0.016). Oxygen saturation was significantly decreased in group C versus group B during procedure with significant lesser improvement in group C after applying rebreathing oxygen face mask at a flow of 7 L/min with no need for intubation (Table 4).
Table (2): Laboratory data of cirrhotic patients who received sedation.
Parameter
Group B
(n=30)
Group C
(n=30)
P-value
Laboratory investigations [mean ± SD]
Hemoglobin [g/dL, mean ± SD]
10.9±1.99
10.7±1.73
0.746
White blood cells [10^3/uL, median (IQR)]
4.9 (4.1 – 6.3)
4.25 (3.3 – 6.7)
0.28
Platelets [10^3/uL, median (IQR)]
92.5 (70.8– 114.3)
106 (71 –138.5)
0.446
INR [mean ± SD]
1.24±0.27
1.39±0.26
0.022
ALT [IU/L, median (IQR)]
33.5 (21.8– 48.3)
30 (19.8 – 37.3)
0.174
AST [IU/L, median (IQR)]
33 (30 –50.3)
34.5(28.8 – 42.3)
0.554
Total bilirubin [mg/dL, median (IQR)]
1.8 (1.1 – 2.7)
1.95 (1.45–2.78)
0.711
Albumin [g/dL, mean ± SD]
2.99±1.73
2.77±0.68
0.188
AFP [IU/mL, median (IQR)]
5 (2–8)
5.5 (2.35 – 13)
0.491
Serum creatinine [mmol/L, median (IQR)]
0.7 (0.5 – 0.8)
0.9 (0.58 –1.1)
0.038
Blood urea nitrogen [mg/dL, median (IQR)]
15 (12.8 – 20.5)
14 (11.8 –19.8)
0.299
Serum sodium [mmol/L, mean ± SD]
134.5±4.06
131.93±4.18
0.019
Serum potassium [mmol/L, mean ± SD]
3.88±0.48
3.96±0.58
0.545
MELD Score [median (IQR)]
11.22 (10.5– 16.3)
12.8 (10.8 –17)
0.132
Child Pugh score [n (%)]
0.258
A
14 (46.7%)
8 (26.7%)
B
10 (33.3%)
15 (50.0%)
C
6 (20.0%)
7 (23.3%)
AFP, alpha-fetoprotein.; ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio; IQR, interquartile range; MELD, Model for End-Stage Liver Disease; SD, standard deviation.
Table (3): Comparison of number connection test between studied groups.
Group A
(n=10)
Group B
(n=30)
Group C
(n=30)
P-value
NCT before
[seconds, mean ± SD]
43.6±6.38
59.23±17.8
68.8±20.49
0.003
NCT one hour after
[seconds, mean ± SD]
40.5±6.91
79.67±30.13
68.8±19.18
<0.001
ΔNCT
[seconds, mean ± SD]
-0.07±0.09
0.33±0.21
0.001±0.07
<0.001
NCT, number connection test; Δ, delta change = [NCT one hour after - NCT before] / [NCT before]
Table (4): Comparison between Group B and C according to blood pressure, pulse and oxygen saturation before, during and after procedure.
Group B
(n=30)
Group C
(n=30)
P-value
Systolic blood pressure [mmHg, mean ± SD]
Before
116.7±10.4
112.8±11.2
0.167
During
109.2±9.7
108.5±9.4
0.778
After
106.5±10.6
111.8±11.1
0.063
Pulse [beats per minute, mean ± SD]
Before
83.66±10.6
81.2±1
0.359
During
91.5±11.2
93.6±15.4
0.548
After
85.9±8
83.1±9.4
0.219
Oxygen saturation [%, mean ± SD]
Before
97.4±1.6
98±1.3
0.116
During
96.4±1.7
94.3±3
0.002
After
97±1.7
97.8±1.2
0.039
SD, standard deviation.
DISCUSSION
Minimal hepatic encephalopathy is indicative of cognitive dysfunction due to cerebral electrophysiological, neurotransmitter, blood flow, metabolism, and fluid homeostatic changes that occurs in CLD patients without clinical evidence of hepatic encephalopathy [12].
The aim of this study is to determine the impact of propofol in comparison to midazolam on the occurrence of sub-clinical hepatic encephalopathy in liver cirrhotic patients undergoing UGE.
In this work we used only the NCT to diagnose MHE because it is easier and has higher validity than other cognitive function tests [13] although it was non-specific and could be affected by other factors such as age of the patient and level of education [14].
We found that most patients with cirrhosis, showed evidence of sub-clinical encephalopathy according to time needed to complete the NCT in comparison to non-hepatic patients before endoscopy similar to other study which reported that 58 patients of cirrhotic patients (95%) had sub-clinical encephalopathy before UGE (NCT: 84.7 ± 77 s; normal less than 30 s) [15].
NCT has been observed to be impaired in elderly [16], but the age of studied patients included in the present study was
In the present study we found that in midazolam group there is a significant increase of the NCT one hour after endoscopy in comparison to the NCT before the procedure. This means that midazolam in the current study exacerbated subclinical hepatic encephalopathy.
This finding agrees with one study which found that number of cirrhotic patients with abnormal NCT showed statistically significant increase after midazolam intake (pre-sedation 33 patients (54.1%); post-sedation 46 patients (75.4%); p<0.001). Also, it showed that the difference between the mean of pre-sedation (43.5 seconds) and post-sedation (60 seconds) NCT times in cirrhotic patients was statistical significance (p=0.001) [17].
Propofol did not worsen MHE in cirrhotic patients at one hour after sedation when compared to midazolam in agreement with other studies [18-21].
Patients who received propofol took shorter time for induction of anesthesia and shorter time of procedure and recovered quickly than patients who received midazolam (p<0.001), so this led to early discharge of the patients after procedure. This finding comes in agreement with some studies which confirmed that propofol was better than midazolam during recovery from sedation for UGE due to worsening of psychometric tests and critical flicker frequency with midazolam [21-24].
The present study agrees with a meta-analysis result of 12 randomized colonoscopy trials showing significant lower side effects of propofol including hypoxemia, hypotension and bradycardia in comparison to benzodiazepines [25].
Also, one study evaluated nurse-administered propofol sedation with assistance of anesthesiologist in an endoscopic center of a private hospital in Japan. Among involved patients, 6.7% had hypoxemia (blood oxygen saturation <90%) and 0.62% developed severe hypoxemia (blood oxygen saturation <85%) required oxygen administration via a nasal cannula, but neither mask ventilation nor endotracheal intubation were needed [26]. Also, Wahab et al. reported hypoxia more frequent in the midazolam group, while no hypoxia was recorded in the propofol and combined propofol and midazolam groups [20].
Similar to ours, one study showed hypotension (systolic blood pressure < 90 mm Hg) in 1.2% of upper endoscopy patients and 3.5% of colonoscopy patients after propofol sedation. However, this hypotension was improved immediately after giving intravenous saline solution [26].
There is still controversy, in spite of several studies, regarding the unsafety of propofol administration by endoscopists. This assumption was raised by anesthesiologists without any scientific evidence [26, 27].
Limitation of current study is the usage of only one psychometric test to label patients with MHE, although the used NCT is considered the standard psychometric test.
Future larger studies are needed to determine the clinical relevance of the present study findings on driving and machinery work.
CONCLUSION
The results of the present study clarified that midazolam exacerbates sub-clinical encephalopathy. The hypotension and tachycardia during the procedure were more significant in midazolam group than propofol group. Subjects receiving propofol showed shorter induction, time of procedure and recovery periods, however for patients’ safety, advanced life support should be available when needed.
ACKNOWLEDGMENT
The authors would like to acknowledge all the participants for their cooperation.
Funding: None.
Conflict of interest:None.
Ethical consideration
This study was approved by Research Ethics Committee of Faculty of Medicine, Ain Shams University following principles of the declaration of Helsinki (FMASU R75/2022). All studied patients signed for informed and written consent.
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