Effect of prophylactic perphenazine on delirium after extubation in severe acute pancreatitis

doi:10.21203/rs.3.rs-4207629/v1

Background: Severe acute pancreatitis (SAP) is a life-threatening condition that can require invasive mechanical ventilation (IMV) to ensure adequate oxygenation and ventilation. However, IMV can cause delirium, which negatively impacts patient outcomes. Perphenazine, an antipsychotic drug that blocks dopamine receptors, can alleviate symptoms such as irritability and restlessness that caused by delirium. This retrospective study aimed to identify risk factors associated with delirium in SAP patients after extubation and withdrawal from IMV, and to determine whether prophylactic use of perphenazine could reduce the incidence of delirium.

Methods: Patients with SAP aged 18-75 years who underwent IMV and were successfully extubated offline after treatment were included. The clinical data were compared between patients who received perphenazine prophylactically or not.

Results: A total of 40 patients were enrolled, with a mean age of 42 years and a male to female ratio of 1.58:1. The incidence of delirium was 22.50%. Univariate analysis and binary logistic regression showed that prophylactic use of perphenazine reduced the incidence of delirium. Fentanyl use was a risk factor for delirium in the univariate analysis. Patients in the delirium group were hospitalized longer than those in the non-delirium group. Prophylactic use of perphenazine might be helpful to reduce in-hospital mortality.

Conclusion:Perphenazine might have a potential effect on post-extubation delirium in SAP patients.

Severe acute pancreatitis

Invasive mechanical ventilation

Delirium

Perphenazine

Severe acute pancreatitis (SAP) is a potentially life-threatening condition, which can lead to organ failure, and respiratory failure is a common manifestation[1, 2]. In these patients, invasive mechanical ventilation (IMV) is often necessary to ensure adequate oxygenation and ventilation[3]. However, IMV can be associated with adverse effects, such as delirium, which can negatively impact patient outcomes[4, 5].

Delirium is a common clinical manifestation characterized by a fluctuating disturbance of consciousness and cognition, perceptual disturbances, psychomotor agitation or retardation, and emotional disturbances. It is especially prevalent in hospitalized patients, particularly the elderly, and can be caused by several precipitating factors, including serious illnesses such as sepsis and stroke, medical interventions such as catheterization and tracheal intubation, physical restraints, surgical anesthesia, certain medications such as sedatives and opioids, pain, environmental changes, dehydration and electrolyte imbalances, and urinary retention or fecal impaction[6].

Perphenazine is an antipsychotic drug that primarily work by blocking dopamine receptors, which can help reduce psychotic symptoms caused by dopamine overactivity[7]. It can also affect other neurotransmitter receptors, such as 5-hydroxytryptamine and acetylcholine receptors, providing a calming effect and alleviating symptoms such as irritability and restlessness, which can potentially prevent the occurrence of delirium. However, the reliability of the drug in improving brain function in patients with critical delirium remains to be investigated[8].

The aim of this study is to identify risk factors associated with delirium in patients with severe acute pancreatitis after extubation and invasive ventilator withdrawal, and to determine whether prophylactic use of perphenazine could reduce the incidence of delirium.

Study subjects

This retrospective study utilized the electronic database of Ruijin Hospital to review cases and collect data. The study included patients with severe acute pancreatitis (SAP) aged 18–75 years who were admitted to the emergency intensive care unit (EICU) within 72 hours of their first onset between January 2018 and December 2021. These patients underwent invasive mechanical ventilation by endotracheal intubation within one week of admission and were successfully extubed offline after treatment. SAP patients were diagnosed based on the Atlanta Guidelines for organ dysfunction, with a modified Marshall score of ≥ 2 and duration of > 48 hours. Pregnant or lactating women, patients with tracheotomy due to prolonged invasive mechanical ventilation, those with malignant tumors, chronic pancreatitis, severe chronic cardiovascular, kidney, or liver diseases were excluded from the study.

All patients received routine treatment, including fasting, etiological management, fluid resuscitation, management of abdominal hypertension, organ function support, and maintenance of internal environment stability. For these patients, when initially using invasive mechanical ventilation, the sedation target was defined as a Richmond Agitation-Sedation Scale (RASS) score ranging from − 2 to -4[9]. As their condition improved, the sedation target gradually shifted to a RASS score of -1 to 0, and sedation drugs were eventually discontinued. The assessment of delirium began after the removal of the endotracheal tube, using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)[10] every 12 hours. Based on whether prophylactic anti-delirium therapy was performed two days before extubation, patients were divided into perphenazine and non-perphenazine groups. Whether to use perphenazine or not mainly depended on the personal experience of the attending physician, and the dosage used was consistently 2mg q12h for two days.

Clinical variable

The clinical variables of each patient were extracted from the electronic database of Ruijin Hospital. Baseline demographic information, including age, sex, etiology, blood routine, biochemical markers, C-reactive protein (CRP), procalcitonin (PCT), Modified Marshall score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and bedside acute pancreatitis Severity Index (BISAP) score, were collected. Other indicators included the duration of tracheal intubation, enteral nutrition initiation time after admission, sedative and analgesic drugs used, incidence of delirium, length of stay and in-hospital mortality.

Statistical analysis

The clinical data were analyzed using SPSS 26.0 statistical software (SPSS, Inc., Chicago, IL). The enumeration data were presented as means(x̅) ± standard deviation (SD) and compared using t-test or Mann-Whitney U test. Categorical data were expressed in frequency and percentage terms and compared using chi-square tests or Fisher's test. Binary logistic regression was used to evaluate the risk factors for delirium in patients with SAP after extubation. P-value < 0.05 was considered statistically significant.

Clinical characteristics of the patients

A total of 40 patients were enrolled, with a mean age of 42 years and a male to female ratio of 1.58:1. There were 9 in the delirium group and 31 in the non-delirium group. The incidence of delirium was 22.50% (9/40). The baseline values of clinical features, including laboratory indicators and disease severity scores on admission, were similar in both groups (Table 1).

Risk factors for delirium in patients with SAP after extubation

A univariate analysis of the effects on post-extubation delirium in SAP patients showed that prophylactic use of perphenazine reduced the incidence of delirium while fentanyl increased the incidence of delirium among pre-extubation sedatives and analgesics (Table 1). The effects of midazolam could not be analyzed because all patients received midazolam. Binary logistic regression was used to correct for the two identified risk factors, using hypertension, serum amylase, pre-albumin, age and APACHEⅡ score (Table 2). Prophylactic use of perphenazine reduced the incidence of post-extubation delirium by a factor of 0.035 with a 95% confidence interval (CI) of 0.002-0.762. Fentanyl was not an independent risk factor.

Influence of delirium on prognosis in patients with SAP after extubation

Patients in the delirium group were hospitalized longer than those in the non-delirium group, but there was no significant difference in in-hospital mortality (Table 3).

Effect of prophylactic use of perphenazine on prognosis of SAP patients with successful extubation

All cases were regrouped into two groups based on prophylactic use of perphenazine. There was no significant difference in baseline clinical characteristics between the two groups at admission (Table 4). However, the in-hospital mortality of patients in the perphenazine group was significantly lower than that in the non-perphenazine group (Table 5).

SAP patients with respiratory failure often require IMV, which can be associated with the development of delirium[11]. Delirium is a common complication in these patients and can significantly affect the patient's prognosis. By identifying risk factors and effective preventive measures, patient outcomes can be improved[12]. This study represents the first investigation into the preventive effect of perphenazine on delirium after extubation in SAP patients.

Recent studies have highlighted the incidence and impact of delirium in SAP patients. A retrospective study found that delirium occurred in 16.98% of SAP patients and was associated with decreased patient satisfaction and longer hospital stay[11]. A prospective observational study reported that delirium occurred in 19.2% of SAP patients and was associated with longer ICU and hospital stay[13]. Delirium was independently associated with a long-term poor prognosis[14]. This means that even if the disease is effectively treated, delirium may cause persistent cognitive impairments, such as memory loss and impaired executive function. And a limited increase in nursing interventions could not reduce the duration of delirium and coma within 28 days in critically ill patients[15].

Therefore, it is crucial to identify risk factors for delirium in SAP patients who require IMV to prevent and manage this complication effectively. In our study, there was a higher rate of delirium due to invasive mechanical ventilation with endotracheal intubation, which is already a risk factor for delirium. In univariate analysis, perphenazine showed an anti-delirium effect, whereas fentanyl caused delirium. After multi-factor adjustment, perphenazine still has protective effect. Other risk factors for delirium in SAP patients that appeared in multiple systematic reviews[16–18], including older age, higher SAP severity scores, and the use of other sedatives and opioids, did not show positive results in our study, possibly due to the small sample size. Older age is a well-known risk factor for delirium in critically ill patients, and it is associated with an increased risk of cognitive impairment and dementia[19, 20]. Higher disease severity scores reflect more severe disease and organ dysfunction, which can increase the risk of delirium due to the systemic inflammatory response and multiorgan failure[21, 22]. The use of sedatives and opioids, which are commonly used in critically ill patients to manage pain, anxiety, and agitation, can also contribute to delirium by impairing cognitive function and increasing sedation depth[23, 24]. Five parameters, hypertension, serum amylase, pre-albumin, age and APACHEⅡ score, were used in the adjustment of P value. This is because the first 3 parameters have a P-value of less than 0.15 in comparison of clinical features, while the latter 2 parameters are common risk factors for delirium in other literature. Therefore, strategies to prevent and manage delirium in SAP patients receiving IMV should focus on minimizing the use of sedatives and opioids, optimizing pain control with non-pharmacological approaches and non-opioid analgesics, and promoting early mobilization and cognitive stimulation.

Delirium may be caused by neuroinflammation, hypoxia, altered energy metabolism, and imbalances in different neurotransmitter pathways[25]. These mechanisms can disrupt normal brain function and lead to confusion, altered consciousness, and other symptoms. But so far, no drugs have been shown to improve the prognosis of patients with delirium. In a multicenter, blind, placebo-controlled trial designed to investigate the effect of haloperidol on delirium in ICU patients, 1000 adult delirious patients admitted to the ICU for an acute condition were randomized to receive intravenous haloperidol or placebo[26], and the result showed that there was no significant difference between haloperidol and placebo in terms of the number of days alive and out of the hospital at 90 days in ICU patients with delirium. In a meta-analysis, melatonin was associated with a reduced incidence of delirium in ICU hospitalized patients, showing its potential to prevent delirium from occurring[27]. But in a recent randomized controlled trial, prophylactic administration of melatonin did not reduce the prevalence of delirium compared with placebo[28]. Dexmedetomidine belongs to the class of drugs known as selective alpha-2 adrenergic agonists. Several clinical trials have investigated its effects on the incidence of delirium in critically ill patients, and the results suggest that dexmedetomidine may effectively reduce the incidence of delirium in this population[29, 30]. Saran et al. reported that quetiapine prophylactic therapy does not reduce the incidence of delirium in hospitalized elderly patients[31]. However, treatment with antipsychotic drugs and antidepressants can alleviate delirium symptoms in some hospitalized patients[32]. In our study, we investigated the effects of prophylactic antidelirium therapy with perphenazine on delirium incidence. Our results showed that the use of perphenazine reduced delirium incidence, but the duration of delirium was not counted due to the small number of cases. There was a decrease in in-hospital mortality in patients treated with prophylactic perphenazine, which was not reported in other literature. We suspect that for specific groups, this reduction in mortality might be due to reduced delirium. Alternatively, it could be due to statistical bias resulting from a relatively small sample size. A prospective randomized controlled trial is needed to confirm our findings.

Limitation

We set very detailed criteria for case enrollment, which, while ensuring consistency of intervention measures in cases, reduced the total number of cases. In the Perphenazine group, only two cases of delirium occurred, making it impossible to compare the duration of delirium between the two groups.

In summary, delirium is a complex condition that can be caused by multiple factors. Delirium can have serious consequences, including an increased number of hospital days. Medical staff should be aware of the risk factors for delirium and take proactive measures to prevent it. Perphenazine might have a potential role in preventing delirium after extubation in SAP patients. Prospective studies should be used to further confirm the effect.

Availability of data

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding

This work was supported by Clinical Technology Innovation Project of Shanghai Hospital Development Center of China (SHDC22021304) to Erzhen Chen.

Author Contributions

TTN and EQM contributed to conception and design of the study. MC and MLY organized the database. TTN, DYZ and YC analyzed and interpreted the data. TTN and DYZ wrote the first draft of the manuscript. YC, ZTY, EZC, and EQM revised the manuscript. All authors read and approved the submitted version.

Acknowledgement

Not applicable.

Ethics approval and consent to participate

The Ethics Committee of Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine approved the study, and informed consent was waived since the data were already generated before the start of the research.

Consent for publication

The authors agreed to publication in the journal.

Competing interests

The authors declare that they have no competing interests.

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Table 1 Comparison of baseline clinical characteristics between delirium group and non-delirium group (n%; ±s)

	Total (n=40)	Delirium group (n＝9)	Non-delirium group (n＝31)	P value
Mean age (years)	41.98±14.27	47.67±13.13	40.32±14.35	0.177
Gender (male%) Body Mass Index (kg/m²) Etiology Biliary Hypertriglyceridemia Alcohol Others Comorbidities	23 (57.50%) 27.78±5.34 18 (45.00%) 17 (42.50%) 1 (2.5%) 4 (10.00%)	6 (66.67%) 27.51±3.65 5 (55.56%) 4 (44.44%) 0 (0.00%) 0 (0.00%)	17 (54.84%) 27.85±5.78 13 (41.94%) 13 (41.94%) 1 (3.23%) 4 (12.90%)	0.527 0.867 0.626
Hypertension (%)	9 (22.50%)	4 (44.44%)	5 (16.13%)	0.073
Diabetes mellitus (%)	12 (30.00%)	4 (44.44%)	8 (25.81%)	0.283
Indicators on admission
White blood cell (×10⁹/l)	13.27±6.40	12.45±2.74	13.51±7.14	0.669
Hemoglobin (g/l)	135.63±28.03	144.67±19.79	133.00±29.75	0.277
C-reactive protein (µg/ml)	220.69±149.49	158.32±102.99	238.80±157.21	0.158
Procalcitonin (ng/ml)	9.42±16.59	10.37±11.93	9.14±17.88	0.847
Serum amylase (U/L)	1030.05±884.41	1502.33±1236.93	892.93±722.83	0.068
Alanine aminotransferase (U/l)	84.80±146.39	126.22±227.63	72.77±115.67	0.514
Total bilirubin (µmol/l)	34.31±41.24	52.96±61.63	28.90±32.61	0.288
Blood urea nitrogen (mmol/l)	8.15±6.25	8.90±5.63	7.93±6.49	0.687
Serum creatinine (µmol/l)	118.48±123.55	107.78±101.48	121.58±130.59	0.772
Albumin (g/l)	34.13±5.17	36.33±7.35	33.48±4.30	0.294
Pre-albumin (g/l)	127.40±56.37	164.67±75.94	116.58±45.34	0.102
Intra-abdominal pressure (mmHg)	14.51±3.77	13.86±4.07	14.70±3.73	0.568
Modified Marshall score	3.35±1.70	3.22±0.97	3.39±1.87	0.802
BISAP score	2.95±0.78	3.00±0.87	2.94±0.77	0.831
APACHEⅡscore	14.93±3.65	13.78±3.87	15.26±3.58	0.290
Enteral nutrition initiation time (day)	4.35±1.63	4.47±1.41	4.26±1.69	0.514
Duration of tracheal intubation (day)	7.45±3.52	6.67±2.35	7.68±3.80	0.456
Use of sedative and analgesic drugs prior to withdrawal from invasive ventilator
Perphenazine	22 (55.00%)	2 (22.22%)	20 (64.52%)	0.025*
Midazolam	40 (100.00%)	9 (100.00%)	31 (100.00%)	/
Dexmedetomidine	18 (45.00%)	4 (44.44%)	14 (45.16%)	0.970
Propofol	25 (62.50%)	7 (77.78%)	18 (58.06%)	0.282
Fentanyl	19 (47.50%)	7 (77.78%)	12 (38.71%)	0.039*
Dormoline	8 (20.00%)	1 (11.11%)	7 (22.58%)	0.410

Note: BISAP score: Bedside Index for Severity in Acute Pancreatitis score, APACHEⅡ score: Acute Physiology and Chronic Health EvaluationⅡ score. *P<0.05 was considered statistically significant.

Table 2 Binary logistic regression analysis of risk factors for delirium in patients with severe acute pancreatitis after extubation

Drug

Drug use

Adjusted OR (95%CI)

P adjusted

Perphenazine

Non-use

Use

1

0.035 (0.002 – 0.762)

0.033*

Fentanyl

Non-use

Use

1

2.607 (0.259 – 26.236)

0.416

P adjusted: assessed by binary logistic regression; adjusted for hypertension, serum amylase, pre-albumin, age and Acute Physiology and Chronic Health EvaluationⅡ score. *P < 0.05 was considered statistically significant.

Table 3 Influence of delirium on prognosis of patients with severe acute pancreatitis after extubation and invasive ventilator withdrawal

Delirium group

(n＝9)

Non-delirium group

(n＝31)

P value

In-hospital mortality n (%)

2 (22.22%)

2 (6.45%)

0.213

Length of stay

81.56±51.28

41.17±23.50

0.047*

Note: *P < 0.05 was considered statistically significant.

Table 4 Comparison of baseline clinical characteristics between perphenazine group and non- perphenazine group on admission (n%; ±s)

	Perphenazine group (n＝22)	Non-perphenazine group (n＝18)	P value
Mean age (years)	41.77±15.41	42.22±13.16	0.923
Gender (male%) Body Mass Index (kg/m²) Etiology Biliary Hypertriglyceridemia Alcohol Others Comorbidities	13 (59.09%) 27.34±3.47 11 (50.00%) 8 (36.36%) 0 (0.00%) 3 (13.64%)	10 (55.56%) 28.30±7.07 7 (38.89%) 9 (50.00%) 1 (5.56%) 1 (5.56%)	0.822 0.579 0.462
Hypertension (%)	4 (18.18%)	5 (27.78%)	0.470
Diabetes mellitus (%)	7 (31.82%)	5 (27.78%)	0.781
Indicators
White blood cell (×10⁹/l)	12.19±5.58	14.60±7.21	0.241
Hemoglobin (g/l)	136.09±25.37	135.06±31.72	0.909
C-reactive protein (µg/ml)	258.33±160.17	174.70±124.50	0.078
Procalcitonin (ng/ml) Serum amylase (U/L) Alanine aminotransferase (U/l) Total bilirubin (µmol/l) Blood urea nitrogen (mmol/l) Serum creatinine (µmol/l) Albumin (g/l) Pre-albumin (g/l) Intra-abdominal pressure (mmHg) Modified Marshall score BISAP score APACHEⅡscore Enteral nutrition initiation time (day) Duration of tracheal intubation (day)	9.93±18.15 1109.45±997.31 101.55±140.70 26.85±29.20 8.76±7.39 142.05±150.13 34.45±4.98 130.86±60.97 14.56±3.82 3.73±2.10 2.95±0.72 15.14±3.64 4.27±1.20 7.14±1.75	8.79±14.96 933.00±740.02 64.33±154.61 43.43±51.85 7.40±4.61 89.67±74.71 33.72±5.51 123.17±51.62 14.45±3.82 2.89±0.90 2.94±0.87 14.67±3.74 4.44±2.06 7.83±4.94	0.833 0.537 0.431 0.210 0.501 0.161 0.662 0.673 0.931 0.101 0.968 0.691 0.744 0.575

Note: BISAP score: Bedside Index for Severity in Acute Pancreatitis score, APACHEⅡ score: Acute Physiology and Chronic Health EvaluationⅡ score. *P<0.05 was considered statistically significant.

Table 5 Effect of prophylactic use of perphenazine on prognosis of SAP patients with successful extubation

Perphenazine group

(n＝22)

Non-perphenazine group

(n＝18)

P value

In-hospital mortality n (%)

0 (0.00%)

4 (22.22%)

0.033*

Length of stay

50.53±36.14

49.93±35.60

0.959

Note: *P < 0.05 was considered statistically significant.

No competing interests reported.

Effect of prophylactic perphenazine on delirium after extubation in severe acute pancreatitis

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Abstract

Background

Methods

Study subjects

Clinical variable

Statistical analysis

Results

Discussion

Limitation

Conclusion

Declarations

References

Tables

Additional Declarations

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