High prolactin levels are associated with more delirium in septic patients

    High prolactin levels are associated with more delirium in septic patients Duc Nam Nguyen MD, Luc Huyghens MD, PhD, Johan Schiettecatte, Johan Smitz MD, PhD, Jean-Louis Vincent MD, PhD PII: DOI: Reference:

S0883-9441(15)00625-5 doi: 10.1016/j.jcrc.2015.12.021 YJCRC 52040

To appear in:

Journal of Critical Care

Please cite this article as: Nguyen Duc Nam, Huyghens Luc, Schiettecatte Johan, Smitz Johan, Vincent Jean-Louis, High prolactin levels are associated with more delirium in septic patients, Journal of Critical Care (2016), doi: 10.1016/j.jcrc.2015.12.021

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ACCEPTED MANUSCRIPT High prolactin levels are associated with more delirium in septic patients Duc Nam Nguyen 1, MD; Luc Huyghens MD, PhD 1; Johan Schiettecatte 2; Johan Smitz, MD, PhD 2; Jean-Louis Vincent, MD, PhD 3.

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1. Department of Critical Care Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit of Brussel, Brussels, Belgium.

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2.Laboratory of Clinical Chemistry & Radioimmunology, Universitair Ziekenhuis Brussel, Vrije Universiteit of Brussel, Brussels, Belgium.

Word counts: Abstract: 167 words Text: 2795 words.

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3.Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Address for correspondence: Duc Nam Nguyen, MD Department of Critical Care Medicine Universitair Ziekenhuis Brussel Laarbeeklaan 101, Brussels 1090, Belgium Phone: 003224775178 Fax: 003224775179 E-mail: [email protected]

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ACCEPTED MANUSCRIPT ABSTRACT Purposes: We investigated whether high prolactin levels were associated with delirium in

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septic patients as neuropsychiatric disorders are frequently associated with

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hyperprolactinemia.

Materials and Methods: Prolactin levels were measured daily for 4 days in 101 patients with

Confusion Assessment Method (CAM-ICU).

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sepsis. Delirium was assessed using the Richmond Agitation Sedation Scale (RASS) and the

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Results: Delirium developed in 79 patients (78%), and was more common in patients older than 65 years. Prolactin levels were higher in patients with delirium than in those without over the four days of observation (p=0.032). In patients with delirium, higher prolactin levels were associated with a lower incidence of nosocomial infection (p=0.006). Multivariable logistic

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regression showed that the SOFA score at ICU admission (odds ratio [OR]: 1.24, 95% CI

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[1.04, 1.48], p= 0.002) and the combined effect of prolactin levels with age (OR: 1.018, 95% CI [1.01, 1.031], p= 0.006) were associated with the development of delirium.

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Conclusions: High prolactin levels may be a risk factor for delirium in patients with sepsis.

Key words: Prolactin, delirium, SOFA score, nosocomial infections, aging.

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ACCEPTED MANUSCRIPT 1. INTRODUCTION Although vital for stimulating cognitive function, motor reflexes, and immunity for host

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survival, stress activation of the hypothalamic-pituitary-adrenal axis (HPA) is commonly

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disturbed in sepsis [1]. The resultant aberrant stress hormone responses, including those of cortisol, catecholamines and prolactin, may be deleterious for the brain and the immune

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system where their specific receptors are abundant [2, 3].

Aberrant stress hormone response and disturbance of the neurotransmission system

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(including dopamine hyperactivity, cholinergic and serotoninergic deficiency) working in concert with hypotension, hypoxia, and excessive brain inflammation are important risk factors in the pathogenesis of cognitive dysfunction or delirium in critical illness [4, 5]. It has been reported that excessive stress cortisol release is immunosuppressive and involved in the

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development of delirium in sepsis, in psychosis, and in Cushing’s disease [6-8].

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Similar to cortisol, prolactin is a stress hormone that can affect behavioral or cognitive function, and is involved in the regulation of the immune system, beyond its sexual

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reproductive and lactogenesis properties [9, 10]. Hyperprolactinemia has frequently been

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reported in neuropsychiatric disorders, including schizophrenia, bipolar disorder, and altered mood [11-14]. It has been also showed that prolactin can have a harmful effect on the brain in experimental studies. In vitro, prolactin can stimulate cytokine release from astrocytes [15]. In rats, prolactin administration can induce a thrombogenic effect and aggravate brain endothelial dysfunction when it passes into the brain [16]. However, unlike cortisol, it is not known whether stress-induced prolactin release has any impact on the brain and cognitive function in clinical sepsis. In this prospective observational study, we investigated the association between prolactin levels and cognitive function in septic patients. We hypothesized that excessive stress-induced prolactin release may be associated with delirium.

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ACCEPTED MANUSCRIPT 2. MATERIALS AND METHODS The study was conducted in a 24-bed multidisciplinary, mixed medical-surgical department of

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intensive care in a university teaching hospital. The Ethical Committee of our hospital

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approved the study and informed consent was obtained from the patients’ relatives and from the control patients.

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2.1. Subjects

All patients admitted to the ICU between May 2010 and September 2012 with a diagnosis of

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sepsis or septic shock as defined according to standard criteria [17] were considered for inclusion. Exclusion criteria included: patients younger than 18 years of age, concomitant treatment interfering with prolactin release (dopamine, levodopa, bromocriptine, metoclopramide, haloperidol, tricyclic antidepressant, antipsychotic drugs), pregnancy,

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cerebral disorder (prolactinoma, seizures, trauma, stroke, hemorrhage, meningitis, post-

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hypophysectomy or other neurosurgery), post-cardiorespiratory arrest, alcohol withdrawal, psychiatric disorder, dementia, disabling neuromuscular disorders, Parkinson’s disease, severe

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hypothyroidism, advanced liver cirrhosis, chronic kidney hemodialysis, and advanced

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malignancy. We also excluded patients who died in the first 24 hours after the onset of sepsis. A control group of 40 age-matched, non-septic patients on the general ward (surgical and medical) who had no organ dysfunction and none of the exclusion criteria was also selected. Sepsis management was conducted according to international consensus guidelines [17]. A mean arterial pressure (MAP) ≥ 65 mm Hg was targeted using fluid administration and norepinephrine (up to 1 µg/kg/min). Dobutamine (at doses up to 10 µg/kg/min) was added if indicated. Mechanical ventilation targeted a tidal volume of 6-7 mL/kg ideal body and a plateau pressure < 30 cmH2O.

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ACCEPTED MANUSCRIPT In patients receiving mechanical ventilation, sedation was initially started using midazolam (up to 0.05 mg/kg/h) or propofol (up to 4 mg/kg/h) and analgesia was achieved

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using fentanyl (up to 0.05 mg/kg/min) or remifentanil (up to 0.75µg/kg/h). The doses of these

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agents were adapted daily to obtain a Richmond Agitation Sedation Scale (RASS) score [18] between 0 and -3. The physician in charge of the patient decided when to withdraw sedation

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and when to wean from mechanical ventilation.

Severity of illness was assessed using the APACHE III score and organ dysfunction

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was assessed on admission and daily thereafter using the Sequential Organ Failure Assessment (SOFA) score. Nosocomial infection was defined as a newly documented episode of sepsis occurring 72 hours after ICU admission, which was associated with a positive microbiological culture or a new lung infiltrate on the chest X-ray, and needed a change in

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antibiotic therapy [19]. A patient who developed shock in association with nosocomial

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infection was said to have recurrent septic shock.

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2.2. Serum prolactin measurements

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Serum prolactin concentrations were measured between 6 and 12 hours after ICU admission and then once daily in the morning for the next three days. Prolactin was also measured daily in the control patients for four days. Prolactin was measured using the Elecsys prolactin II assay on a Cobas 6000 instrument (Roche Diagnostics, Mannheim, Germany) with a withinrun coefficient of variation < 3% and a between-run coefficient of variation < 4% (range 266 to 13896 pmol/L). Normal values in our laboratory are 176-797 pmol/L for males and 1471044 pmol/L for females. The polyethylene glycol precipitation (PEG) test was used to detect macroprolactin in all blood samples with a prolactin concentration > 2043 pmol/L [20]. Blood samples with a prolactin recovery after PEG of < 40% (the percentage that contained ≥ 60% of macroprolatin), were excluded from the analysis.

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ACCEPTED MANUSCRIPT 2.3. Delirium assessment and treatment From ICU admission until ICU discharge, the Confusion Assessment Method in the ICU

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(CAM-ICU) and the RASS were assessed twice daily by the nurse or physician in charge of

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the patient, who was not aware of the prolactin results. In sedated patients, CAM-ICU assessment was started 24 hours after sedation withdrawal. A diagnosis of delirium was

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considered when the RASS score was > -3 and the CAM-ICU was positive for at least two consecutive days. When a positive CAM-ICU was combined with a RASS score of -2 to -1

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the patients were said to have hypoactive delirium and when combined with a RASS score of 1 to 5, they were classified as having hyperactive delirium. The presence of delirium was evaluated at times when the patient was not undergoing any stressful event (physiotherapy, weaning from mechanical ventilation or any medical invasive procedure) to avoid an effect on

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prolactin release and a false positive CAM-ICU result. When indicated, the physician in

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charge of the patient performed brain computed tomography (CT) in delirious patients to exclude stroke or hemorrhage.

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Hyperactive delirium was treated with an antipsychotic drug (haloperidol or

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dehydrobenzperidol) or with an α2-receptor agonist (clonidine or dexmedetomidine) or both. All sedative agents were avoided in hypoactive delirium. Non-pharmacological therapies of delirium, including early mobilization and prevention of sleep deprivation, were used in all patients.

2.4. Statistical analysis The statistical analysis was performed with SPSS version 21.0 (SPSS, Chicago, IL). A Chisquare test or Fisher’s exact test was used for comparisons of categorical variables when appropriate. Continuous variables underwent logarithmic transformation to assume a normal distribution. Analysis of variance (ANOVA) for repeated measures with Bonferroni test for

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ACCEPTED MANUSCRIPT post-hoc comparisons adjusting for age and sex or a Student t-test was used for comparisons between groups. The correlation between continuous variables was evaluated with the

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Pearson or Spearman correlation test when appropriate.

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A multivariable binary logistic regression model adjusted with stepwise selection of covariates (prolactin levels at admission, CRP levels at admission, age, sex, the admission

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SOFA score, the duration of sedation, the administration of midazolam and fentanyl as binary variable, and one interaction term: age x prolactin levels at admission) was used to determine

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the risk factors associated with the development of delirium. The model was selected based on Akaike criterion values. Variables with a univariate logistic regression chi-square p-value < 0.2 were added and retained in the multivariable model at p-values ≤ 0.05. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were calculated for

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the logistic regression model and to determine the cut-off value of prolactin associated with

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delirium.

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3. RESULTS

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Statistical significance was considered at a two-sided p-value < 0.05.

3.1 Patient characteristics A total of 150 consecutive patients with sepsis were enrolled in the study. Forty-nine patients were excluded, including those who died without proper neurological and cognitive evaluation under sedation, so that 101 patients were included in the analysis (Figure 1). Of these 101 patients, 98 patients (97%) were sedated and receiving mechanical ventilation, and 79 (78%) developed delirium: hyperactive in 40 [51%] and hypoactive in 39 [50%]. The median duration of delirium was 6 [4, 12] days. Brain CT detected stroke or hemorrhage in 5 (all hypoactive) out of 18 delirious patients.

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ACCEPTED MANUSCRIPT The patients’ characteristics are shown in Table 1. Patients who developed delirium were older (66 ± 13 vs. 59 ± 17, p= 0.047) and had higher APACHE III scores (85 ± 29 vs. 67

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± 24, p= 0.018) than patients without delirium.

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During the ICU stay, patients with delirium were more likely to develop nosocomial infection and recurrence of septic shock than those without delirium. They also more

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frequently developed critical illness polyneuromyopathy, had longer ICU stays and higher

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ICU mortality rates (Table 2).

3.2 Prolactin levels, SOFA score, and nosocomial infection. Septic patients had higher prolactin levels at admission (881 ± 92 vs. 462 ± 51 pmol/L, p= 0.01) and over the subsequent three days than did the control subjects. There were no

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differences in prolactin levels according to sex.

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Patients with delirium had higher prolactin levels (p= 0.032, Figure 2) than those without delirium after adjusting for age and sex. Higher total SOFA scores, serum creatinine,

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and renal SOFA scores were also observed in patients with than those without delirium at ICU

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admission and three days after admission (Table 3). However, prolactin levels were lower throughout the four days of observation (p= 0.006, Figure 3) in patients with delirium who developed nosocomial infection than in those who did not, although there were no differences in total SOFA scores, renal SOFA score or serum creatinine. There was a significant correlation between prolactin levels and the duration of delirium (r=0.49, p=0.004), serum creatinine levels (r=0.4, p=0.001), and the renal SOFA score (r=0.4, p=0.001) but not with age, APACHE III or total SOFA scores. A prolactin cut-off value of 450 pmol/L predicted the development of delirium with a sensitivity of 65% and a specificity of 63%. An age cut-off value of 65 years predicted delirium with a sensitivity of 63% and a specificity of 64%. In the multivariable binary

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ACCEPTED MANUSCRIPT logistic regression model, the admission SOFA score (odds ratio [OR]: 1.24, 95% CI [1.04, 1.48], p= 0.002) and the combined effect of prolactin with age (OR: 1.018, 95% CI [1.01,

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1.031], p= 0.006) were independently associated with development of delirium. The AUC of

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this model was 82% (95% CI: 69, 89).

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ACCEPTED MANUSCRIPT 4. DISCUSSION In this study, delirium occurred in two-thirds of septic patients and was associated with

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increased ICU mortality and morbidity, including a higher incidence of nosocomial infections

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as previously reported by other authors [18, 21, 22]. Our new finding is that elevated prolactin release may be involved in the development of delirium in septic patients.

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Although known to down-regulate inflammation and stimulate host immunity in sepsis, when released in excess from the adrenals (cortisol, catecholamines) and the pituitary

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(prolactin and growth hormone), stress hormones may have a deleterious effect on cognitive function [1-3]. It has been reported that excessive cortisol or catecholamine release is involved in the development of delirium in severe sepsis, Cushing’s disease, psychosis and schizophrenia [6, 8, 23]. These factors may contribute to the development of delirium in

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sepsis, in addition to other aspects, including cholinergic and serotonin neurotransmitter

hypoxia [4, 5, 24].

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deficiency, brain inflammation, the use of sedatives (benzodiazepines), hypotension and

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The use of midazolam and fentanyl for sedation and analgesia could potentially

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aggravate the development of delirium but was unlikely to have significantly influenced our results because the mean doses administered and the length of sedation were similar in patients who developed delirium and those who did not. Moreover, the daily titration of the doses of these drugs to obtain a RASS score close to 0 reduced the risk of their accumulation, especially in patients with acute kidney injury (AKI). Continuous renal replacement therapy (CRRT) when indicated can also remove the active metabolites of these drugs in the serum [25, 26]. Patients with delirium had higher APACHE and SOFA scores and also had higher prolactin levels than other patients. However, these hormone levels were associated with the duration of delirium but not with the severity scores or the inflammatory biomarker, CRP.

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ACCEPTED MANUSCRIPT Other known stimulating factors of prolactin release - obesity, opiates and norepinephrine administration in shock were also not associated with delirium [27-29]. Our results suggest

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that patients with delirium had greater stress activity combined with HPA dysfunction and

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aberrant prolactin release. Prolactin can influence host behavior or cognitive function by acting on the brain limbic system and the prefrontal cortex, where its receptors are abundant

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[10, 30]. Excessive prolactin release may be harmful for the brain, already injured by the effects of the sepsis process [5].

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Prolactin secretion is essentially regulated by an inhibitory effect of dopamine release from the hypothalamic dopaminergic neurons [10, 31]. High prolactin levels induce brain dopamine hyperactivity, which, in turn, could induce cognitive dysfunction or delirium, as dopamine contributes to control host motor activity and behavior [32, 33]. Measurement of

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serum dopamine is impractical but previous clinical reports indirectly support this hypothesis

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by showing that dopamine or prolactin antagonist treatment (e.g., haloperidol or bromocriptine) improved symptoms in neuropsychiatric and ICU patients, respectively, but

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dopamine agonist treatment (levodopa) aggravated cognitive dysfunction in patients with

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Parkinson’s disease [34-36]. Moreover, Sommer et al. showed that dopamine administration aggravated delirium, necessitating more haloperidol treatment in ICU patients [37]. Prolactin has proinflammatory actions and may enhance a hypercoagulability thrombogenic state and aggravate brain endothelial dysfunction after passing into the brain [16]. In vitro, prolactin triggered release of proinflammatory interleukins from astrocytes [15]. Prolactin can enhance thrombogenesis associated with platelet reactivity in acute stroke and in post-partum females [38-40]. Finally, prolactin aggravates sleep deprivation, which is a contributing factor for ICU delirium [41]. In rats, Roky et al. previously showed that prolactin administration decreased the paradoxical sleep duration by interacting with the serotonin neurons at the preoptic area or the dorsomedial hypothalamic nucleus [42].

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ACCEPTED MANUSCRIPT The effects of prolactin were more pronounced in patients older than 65 years old, although the prolactin cut-off value of 450 pmol/L associated with delirium still remained

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within the normal range. Older patients, who are commonly affected by preexisting cognitive

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impairment due to atherosclerosis and degenerative diseases, may be more sensitive to the effects of prolactin and are more vulnerable to delirium than younger patients [5, 22].

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Moreover, an accentuated neurotransmission disturbance occurring with aging promotes high prolactin levels, including a decrease in hypothalamic dopamine neurons, a reduction in

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serotoninergic response, and an impairment of the negative HPA feed-back [43]. Reduced renal metabolism could be another cause of high prolactin levels in patients with delirium, because the levels of this hormone have been shown to be higher in patients with AKI or chronic renal failure (CRF) [44, 45]. However, the latter was an exclusion

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criterion for our study. Moreover, in patients with AKI or CRF, Grezesczak et al. and

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Sievertsen et al. reported higher prolactin levels after administering dopamine or chlorpromazine (prolactin stimulant) than in other patients. These authors concluded that this

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higher prolactin response was due to a refractory effect and impaired inhibitory dopamine

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effects on pituitary prolactin rather than a reduction in renal metabolism [46, 47]. In rodents with AKI, Dobbie et al. also showed that high prolactin levels were associated with a defect in renal prolactin binding receptors but not a reduction in metabolism [48]. We also found that in patients with delirium, those who developed superinfection had lower prolactin levels than those who did not. Similarly, Felmet et al. previously reported in pediatric patients that hypoprolactinemia was associated with a higher incidence of nosocomial infection [49]. Pituitary dysfunction with reduction of prolactin release [50] and aberrant dopamine hyperactivity were the plausible causes for the lower hormonal levels in these patients [51]. Low prolactin levels and dopamine hyperactivity can impair Tlymphocyte function [52, 53], which may promote an immunosuppressive state and the

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ACCEPTED MANUSCRIPT development of nosocomial infections in delirious patients. Although patients without delirium had lower prolactin levels, they were less likely to develop ICU superinfections than

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were patients with delirium. This may be simply due to their lower illness severity and their

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shorter length of ICU stay.

Our study has several limitations. No levels of dopamine or other neurotransmitters

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were measured to confirm the interference effect between prolactin and dopamine in delirium. Other stress hormones, including cortisol and thyroid hormones were also not measured. In

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addition, no direct deleterious effect of prolactin on cognitive function could be evaluated by neurophysiological studies. Our observational study thus provides evidence of an association between prolactin and delirium but not of causality and the harmful effect of prolactin needs

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be confirmed in further investigations.

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CONCLUSION

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High prolactin levels may be a risk factor for delirium in patients with sepsis.

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Conflicts of interest

The authors have no conflicts of interests.

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ACCEPTED MANUSCRIPT Table 1 Characteristics and comorbidities of the patients on ICU admission

n= 101

Mean blood pressure, mm Hg

85 ± 32 258 ± 158 70 ± 16

38/63 (38/63)

Shock, n (%)

MA NU

Female/male, n (%)

86 (85)

Medical/surgical patients, n (%) Sepsis etiologies : Bronchopneumonia, n (%) Other, n (%) Gram-positive, n (%)

CE

Unknown, n (%)

PT

Gram-negative, n (%)

65/36 (65/36) 66 (65)

ED

Peritonitis, n (%)

Comorbidities:

66 ± 14

SC

Age, years (mean ± standard deviation) APACHE III scores (mean ± standard deviation) paO2/FiO2 ratio

RI P

T

Characteristics and comorbidities

17 (17) 18 (18) 49 (49) 33 (33) 19 (19) 24 (24)

Obesity (Body mass index > 30), n (%)

23 (23)

Arterial hypertension, n (%)

40 (40)

Diabetes, n (%)

20 (20)

Alcohol abuse, n (%)

16 (16)

AC

Active smoking, n (%)

History of brain disorder (stroke, bleeding or degenerative disease), n (%)

23 (23)

22

ACCEPTED MANUSCRIPT Table 2. ICU treatments and outcomes according to the presence or not of delirium

No-Delirium n=22 (22%)

15 ± 13

Delirium n=79 (79%)

p

17 ± 14

0.572

9±7

11 ± 8

0.442

20 (91)

77 (97)

0.206

3.4 ± 2.9

3.4 ± 2.9

3.5 ± 2.9

0.984

97 (96)

20 (91)

77 (97)

0.206

1.6 ± 1.7

1.64 ± 1.9

1.36 ± 1

0.581

9 (9)

1 (6)

8 (10)

0.679

6±5

3±3

6±6

0.111

67 (66)

16 (73)

51(65)

0.473

Septic shock recurrence, n (%)

29 (29)

1 (4)

28 (35)

0.001

Nosocomial infection, n (%)

59 (58)

8 (40)

51(80)

0.001

Critical polyneuro-myopathy, n (%)

58 (57)

7 (32)

51 (65)

0.006

ICU stay, days

24 ± 17

18 ± 14

26 ± 18

0.007

ICU mortality, n (%)

47 (47)

5 (23)

42 (53)

0.014

9±7

Midazolam use, n (%)

97 (96)

MA NU

Sedation length, days

Mean dose of midazolam over the first 4 days (mg/hour)

ED

Fentanyl use, n (%) Mean dose of fentanyl over the first 4 days

Propofol use, n (%)

CE

Vasopressor use length, days

PT

(mg/hour)

Norepinephrine (> 0.1 µg/kg/min), n (%)

AC

15 ± 15

SC

Mechanical ventilation, days

T

n= 101

RI P

ICU treatments and outcomes

23

ACCEPTED MANUSCRIPT Table 3. Biomarkers, SOFA score, and cardiac index on ICU admission and four days after

No-delirium n= 22 (22%)

SC

n= 101

MA NU

Biomarker levels and SOFA score

RI P

T

admission

At ICU admission

Delirium n= 79 (78%)

p

Prolactin, pmol/L

996 ± 1151

669 ± 881

1026 ± 1133

0.049

CRP, mg/dl

210 ± 127

232 ± 123

220 ± 122

0.697

9±4

7±3

10 ± 3

0.010

0.9 ± 0.7

0.4 ± 0.7

1 ± 1.2

0.007

1.28 (0.85, 2)

0.8 (0.6,1.2)

1.4 (1, 2.4)

0.002

842 ± 907

607 ± 773

910 ± 936

0.041

168 ± 97

151 ± 87

173 ± 100

0.392

Total SOFA score

8±4

5±4

9±4

0.002

Renal SOFA score

1±1

0.2 ± 0.9

1 ± 1.2

0.004

Creatinine, mg/dl

1.1 (0.79, 2.29)

0.76 (0.63, 1)

1.21 (0.85, 2.57)

0.001

ED

Total SOFA score Renal SOFA score

PT

Creatinine, mg/dl

Prolactin, pmol/L

AC

CRP, mg/dl

CE

At day four

24