Effect Of Exogenous Melatonin on the Incidence of Delirium and Its Association with Severity of Illness in Postoperative Surgical ICU Patients

Dr. Kriti Gupta, MD

Dr. Vipin K. Singh, MD

Dr. Zia Arshad, MD*

Dr. G. P. Singh, MD

*Corresponding Author

Department of Anaesthesiology

King George’s Medical University

Lucknow UP, India 226003

Abstract 

Background: Delirium is common in critically ill intensive care unit (ICU) patients and has been documented in up to 87 percent of patients. Sleep deprivation and delirium have been associated. Alteration of melatonin production has been associated with delirium. Melatonin acts via melatonin receptors present in the suprachiasmatic nuclei (SCN) and promotes sleep by attenuating the wake-promoting signal from the SCN.

Objective: To determine the relationship between exogenous melatonin and the incidence of delirium and its association of with severity of illness, measured in term of APACHE II, procalcitonin level at the time of admission and daily SOFA score.

Patients and Methods:

Design: Randomised placebo-control study.

Setting: the study was conducted in critical care setting in a tertiary level ICU.

Participants: Postoperative patients age between 20-60 years who are going to be ventilated more than 48 hours without any contraindication to enteral medications.

Interventions: Study group received melatonin 5 mg through the enteral route.

Main outcome measures: To determine the effect of exogenous melatonin on the incidence of delirium in postoperative patients who require mechanical ventilation for more than 24 hours. The secondary outcome measures are procalcitonin (PCT) value at admission and disease severity scores like APACHE II and SOFA.

Results: No statistically significant difference was found in admission incidence of delirium or procalcitonin. Age was higher in those patients that developed delirium (p < 0.05).

Conclusions: Although the incidence of delirium is not affected by exogenous melatonin or higher APACHE scores, it had a significant correlation with higher procalcitonin, that in turn indicated an association with delirium and sepsis. It was found that there is increased risk of developing delirium with increasing age.

Key words: delirium, intensive care unit, sedation, melatonin, APACHE II, procalcitonin,

Introduction

Delirium is defined as “A disturbance in attention (i.e., reduced ability to direct, focus, sustain and shift attention) and awareness (reduced orientation to the environment)” (1). Delirium is extremely prevalent in hospitalized patients; it affects 10%–24% of the adult general medicine population and 37–46% of the general surgical population. Delirium has been documented in up to 87 percent of patients in the intensive care unit (ICU) (2). Multiple etiologies have been hypothesized to be causing delirium. Some of these are central cholinergic deficiency, reduced GABA activity, abnormal serotonin and melatonin pathways, cerebral hypo perfusion and neuronal damage due to inflammation (3,4). Acute Physiology and Chronic Health Evaluation II score (APACHE II) and the Sequential Organ Failure Score (SOFA) score have been found to aid in the prediction of delirium in the critically ill.

It has been demonstrated that pattern of secretion and concentration of melatonin are altered in critically ill patients (5). Melatonin release from the pineal gland is also decreased due to surgical stress and hence its potential use in postoperative delirium (6). Sepsis-associated delirium is a cerebral manifestation commonly occurring in patients with other infection-related organ dysfunctions and is caused by a combination of neuroinflammation and disturbances in cerebral perfusion (7). Procalcitonin is a helpful biomarker for early diagnosis of sepsis in critically ill patients (8).

Melatonin acts via melatonin receptors present in the suprachiasmatic nuclei (SCN) and promotes sleep by attenuating the wake-promoting signal from the SCN (9,10). Bioavailability of melatonin is excellent as demonstrated by supraphysiological level after exogenous supplementation (11).

The Confusion Assessment Method (CAM) is a diagnostic instrument used to screen and diagnose delirium in ICU. The CAM diagnostic algorithm is comprised of four components: (1) an acute (4) an altered level of consciousness. The diagnosis of delirium is based on the presence of both component 1 and 2, and either 3 and 4 (12).

Objective

The primary objective of the study was to determine the efficacy of exogenous melatonin in preventing delirium in postoperative patients admitted in ICU, as well as to compare the outcome by comparing the incidence of delirium and length of ICU stay in two groups. The secondary objective is to determine the association of delirium with severity of illness, which was measured in term of APACHE II and Procalcitonin level at the time of admission and daily SOFA scoring.

Methods

We performed a randomized, placebo-controlled study on postoperative patients admitted in our 20-bed tertiary level ICU. Inclusion criteria included adult postoperative patients requiring mechanical ventilation for more than 48 hours who were able to receive medication by the enteral route. Exclusion criteria included unwillingness to participate; sensitivity or history of allergic reaction to melatonin supplements; pregnancy; paralytic ileus; patients not expected to survive >48 hours; preexisting pathologies including cognitive dysfunction, dementia, psychiatric disorders or sleep disorders; history of head injury, substance abuse or withdrawal; and patients with hearing impairments.

Patients were randomized into two groups of 70 patients each with a sealed envelope randomization method. The study group received melatonin 5 mg via the enteral route at 8 pm every day and the control group received placebo (1 gm lactose powder) through a nasogastric tube until ICU discharge/transfer. APACHE II and procalcitonin (PCT) levels were recorded at admission, and SOFA scores were calculated daily. Delirium preventive measures including decreased light, noise, and regular patient orientation were applied uniformly in both groups. On the day of discharge/transfer the patients were evaluated using the CAM-ICU (Confusion Assessment Method) scale. The patients were categorized as “Delirious” or “Not Delirious” on the basis of the results from the CAM-ICU scale (12). Results were analyzed by comparing the incidence of delirium, length of ICU stay, APACHE II, SOFA Score and PCT value at the time of admission.

Results

A total of 140 adult post-operative patients transferred to the ICU who were ventilated more than 48 hours were evaluated. Table 1 contains the demographics of the study population.

Table 1: Between Group Comparison of Demographic Profile

Mean age of patients enrolled in the study was 38.70±11.56 years. Difference in age of patients in Group A (38.46±11.87) and Group B (38.94±11.33) was not statistically significant.

APACHE II scores did not differ at admission (Table 2).

Table 2: Between Group Comparison of APACHE II Score

Procalcitonin levels did not differ at admission (Table 3).

Table 3: Between Group Comparison of Procalcitonin (ng/ml)

Range of procalcitonin levels of patients of both the groups was 0.2-25.60 ng/ml. Though mean procalcitonin levels of patients of Group B (5.76±6.37 ng/ml) were found to be higher than that of Group A (4.81±6.60 ng/ml) yet this difference was not found to be significant statistically.

Duration of ICU stay was 4 to 27 days. Though mean ICU stay of patients of Group A (9.29±4.57 days) was higher than that of Group B this difference was not found to be significant statistically.

SOFA score of 56 patients of Group A and 55 patients of Group B could be assessed. Median SOFA score of patients of both the groups was 2.00, mean SOFA score of patients of Group A was 2.70±2.20 (range 0-9) while that of Group B was 2.53±1.63. On comparing SOFA score of patients of above two groups, difference was not found to be significant statistically.

CAM ICU score of 111 patients could be assessed. The majority of overall (68.5%) as well as Group A (76.8%) and Group B (60.0%) had negative CAM ICU scores. Though a higher proportion of Group B as compared to Group A had a positive CAM ICU score (40.0% vs. 23.2%), this difference was not found to be significant statistically.

There was no significant difference in the mortality of non-delirious patients.

Patients with delirium as compared to non-delirium had significantly higher values of APACHE-II (20.57±6.26 vs. 18.42±7.14) and significantly higher procalcitonin levels (5.84±6.25 vs. 3.42±6.57 ng/ml).

Table 4: Association of Delirium with Demographic Profile

 

Patients with delirium were found to be older as compared to non-delirium (41.57±9.99 vs. 35.87±11.81). This difference was found to be significant statistically. Proportion of females was higher among delirious as compared to non-delirious patients (54.3% vs. 47.4%), but this difference was not found to be significant statistically.

Delirium was less prevalent in Group A (16.6 percent) than Group B (31.4 percent), although the difference was not statistically significant. Melatonin administration did not significantly affect any of the other outcomes (p>0.05, all comparisons).

Discussion

Delirium is prevalent in all spheres of hospitalization, medical and surgical patients, more prominently in patients admitted to intensive care units. Owing to its multifactorial etiopathogenesis, multiple pharmacological and non-pharmacological methods have been described in various literatures for prevention and treatment of delirium.

Delirium is associated with various complications which may result in unfavorable outcomes. These complications may vary from minor complications like self-extubation, removal of catheters, weaning failure, increase length of ICU stay to increased mortality. Ely and coworkers(13) studied 275 mechanically ventilated medical ICU patients and determined that delirium was associated with a threefold increase in risk for 6-month mortality after adjusting for age, severity of illness, co-morbidities, coma, and exposure to psychoactive medications. The commonest factors significantly associated with delirium are dementia, increased age, co-morbidities, severity of illness, infection, decreased day to day activities, immobilisation, sensory disturbance, urinary catheterization, urea and electrolyte imbalance and malnutrition (14).

Frisk et al. (15) in 2004 conducted a study to assess the biochemical indicators of circadian rhythm of patients admitted in ICUs and found altered secretion patterns and reduction in the urinary metabolite of melatonin, 6-SMT (6-sulphatoxymelatonin). This indicated the possible disruption of this neurohormone in patients admitted in intensive care units. Andersen et al. (16)  concluded that exogenous melatonin could be utilized to alleviate preoperative anxiety in surgical and critical care patients and more importantly, to decrease the emergence of delirium in the early postoperative period. In our study, 140 adult post-operative patients were studied to establish the preventive role of melatonin in delirium. Aghakouchakzadeh et al. (17)  in 2017 conducted a comprehensive review to determine the effect of melatonin on delirium; they concluded that because exogenous melatonin can improve circadian rhythm and prevent delirium, melatonin supplementation could improve or manage delirium in the intensive care unit. Similarly, Yang et al. (18) in their review had found substantial preventative effects of melatonin on delirium .This investigation established a reason for the practice recommendations to recommend melatonergic medications for delirium prevention.

Out of 140 patients that we studied, 29 patients died during the trial, 35 were diagnosed with delirium and 76 had no delirium. Delirium was less prevalent in Group A (16.6 percent) than Group B (31.4 percent), although the difference was not statistically significant. This reduction is similar to the results found by Nishikimi et al. (19) in who found the melatonin agonist to be related to a trend toward shorter ICU stays, as well as significant reductions in the occurrence and duration of delirium in patients admitted to the ICU.

Sepsis and inflammation are important etiologies of delirium. Inflammatory biomarkers (procalcitonin and erythrocyte sedimentation rate) can be predictive of acute brain dysfunction and delirium. Hamza et al.  (20) procalcitonin was significantly higher in their delirious group in univariant (0.9±0.6 vs. 0.4±0.4ng/mL, P<0.001) and multivariate analysis (OR= 35.59, CI (7.73- 163.76)). Similarly, McGrane S et al. (21) conducted a study in 87 non-intensive care unit (ICU) cohorts and found that higher levels of procalcitonin were associated with fewer delirium/coma-free days (odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3 to 1.0; P = 0.04). Our study showed similar results with significantly higher procalcitonin levels in patients with delirium than those without delirium (5.84±6.25 vs. 3.42±6.57 ng/ml).

The Acute Physiology and Chronic Health Evaluation II score (APACHE II) provides a classification of severity of disease and is particularly used in the ICU to predict mortality. In our study, APACHE II scores were calculated for each patient at their admission in the ICU. The range of APACHE-II score of patients enrolled was 6 to 38. Patients of Group A and Group B had comparable APACHE-II Score (21.07±8.17 vs. 21.84±7.81). Patients with delirium as compared to non-delirium had higher values APACHE-II scores (20.57±6.26 vs. 18.42±7.14). This was similar to the findings of Hamza SA et. al.(17), who, in their observational study of 90 patients, found not only have higher APACHE scores but also that the APACHE-II scores had significantly high diagnostic performance in discrimination of delirium (AUC = 0.877, P= <0.001).

Another clinically important score is the Sequential Organ Failure Score (SOFA) score used to sequentially assess the severity of organ dysfunction in critically ill patient ,  is an objective score that calculates the number and the severity of organ dysfunction in six organ systems (respiratory, coagulation , liver, cardiovascular, renal, and neurologic). In a prospective cohort study on 400 consecutive patients admitted to the ICU Rahimi-Bashar et al. (22) found the SOFA scores were significantly higher in those with delirium (7.37 ± 1.17) than those without delirium (4.93 ± 1.70). Similarly in our study, SOFA score of patients with delirium (4.49±1.63) was found to be significantly higher than that of non-delirium (1.75±1.37). Hence the elevated SOFA and APACHEII scores in the delirium can assist in identifying at-risk patients for delirium and hence allow interventions to improve outcomes. 

Aging is often associated with a disruption of the normal circadian cycle, which can also result in delirium. Thus, melatonin and its agonist may have a more significant influence on delirium in the elderly than in the young, Abbasi et al. (23) discovered that delirium is uncommon in a relatively young group. Thus, the relatively young age of our study sample and the enhancement of ICU care (such as decreased light, noise, and regular patient orientation) are the primary reasons for our study's low prevalence of delirium. Additionally, we found patients with delirium were older as compared to non-delirium (41.57±9.99 vs. 35.87±11.81).

As previously stated, the potential benefit of exogenous melatonin supplementation in reducing delirium incidence has been evaluated in non-ICU settings as well. While both the Sultan (24) and Jonghe (25) investigations examined whether melatonin may help postoperative patients avoid delirium, the de Jonghe study employed six times the amount of melatonin used in the Sultan study (3 mg versus 0.5 mg, respectively).

We suggest that individuals at risk of developing delirium, such as the elderly, should be investigated in future researches. Also, further studies are required comparing subgroups of medical, surgical, and trauma patients to determine which patients will benefit most from exogenous melatonin administration. Because plasma and urinary levels of melatonin are directly related to its concentration in the central nervous system, we also recommend monitoring melatonin levels in plasma or urine during the study and for follow-up to ascertain which subgroup of patients benefited most from exogenous melatonin supplementation to prevent delirium.

Conclusion

The study demonstrates there is decreased incidence of delirium in the patients who received exogenous melatonin, although this difference was statistically not significant (p=0.057). There was a statistically significant association of age with development of delirium (p=0.015). It has also been observed that the higher procalcitonin levels are associated with increased incidence of delirium (<0.001).

References

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Cite as: Gupta K, Singh VK, Arshad Z, Singh GP. Effect Of Exogenous Melatonin on the Incidence of Delirium and Its Association with Severity of Illness in Postoperative Surgical ICU Patients. Southwest J Pulm Crit Care Sleep. 2022;25(2):7-14. doi: https://doi.org/10.13175/swjpcc030-22 PDF 

Corticosteroids and Influenza A associated Acute Respiratory Distress Syndrome

Philippe R. Bauer, MD, PhD

Vivek N. Iyer, MD, MPH

Pulmonary and Critical Care Medicine

Mayo Clinic

Rochester, MN USA

Abstract

The use of corticosteroids remains controversial in influenza infection, especially with lower respiratory tract infection. We present a case of moderate acute respiratory distress syndrome (ARDS) associated with influenza A that showed a dramatic improvement with combined corticosteroids and antiviral therapy. Host defense against virus infection consists of both innate and adaptive immune responses. An exuberant immune response to the primary pathogen leads to ‘collateral’ lung damage resulting in ARDS.  The use of corticosteroids to modulate this excessive immune response, although intuitive, has been associated with increased mortality when administered early in the course of severe influenza A pneumonia. The administration of corticosteroids in this case was associated with a dramatic and unequivocal improvement. This unique case highlights the potential benefits of corticosteroids use in influenza A associated ARDS and may challenge clinicians to rethink current recommendations that specifically discourage corticosteroids use in patients with Influenza A associated ARDS.   

Introduction

The impact of corticosteroids on clinical outcome in patients with influenza A associated respiratory failure is unclear (1). Retrospective studies suggest an adverse effect from early parenteral corticosteroids use in patients with pandemic influenza infection. On the other hand, in immunosuppressed patients, high dose corticosteroid given at the time of diagnosis of influenza was associated with a reduced risk for mechanical ventilation, without increased adverse effects other than delayed viral clearance. In general, the effect of corticosteroids on acute respiratory distress syndrome (ARDS) is controversial and its use is not routinely recommended. The adjunctive use of prednisone during the early phase of community-acquired pneumonia may actually reduce the development of ARDS (2). In severe influenza, early corticosteroids showed no evidence of benefit and suggested potential harm (3). We present a case of moderate ARDS associated with influenza A that showed a dramatic and unequivocal improvement after initiation of corticosteroids.

Abbreviations:

APACHE: Acute Physiology and Chronic Health Evaluation

ARDS: Acute Respiratory Distress Syndrome

ICU: Intensive Care Unit

PCR: Polymerase Chain Reaction

SOFA: Sequential Organ Failure Assessment

Case Report

A 62-year old male, nonsmoker, with a history of hypertension, dyslipidemia and depression, presented in March 2014 with chills, fever and nonproductive cough; he was initially treated for ‘bronchitis’ as an outpatient with levofloxacin. He had not received the influenza vaccine. Three days later, he developed acute hypoxemic respiratory failure with bilateral pulmonary infiltrates and was hospitalized elsewhere. Influenza testing was negative and he was started on piperacillin/tazobactam and azithromycin. He was transferred to our facility the next day because of worsening respiratory status. Initial heart rate was 80 bpm, blood pressure was 120/60 mm Hg, respirations was 22/min, and temperature was 37.7 ºC. The Acute Physiology and Chronic Health Evaluation (APACHE) IV score was 55 and the Sequential Organ Failure Assessment (SOFA) score was 8. His presentation was consistent with moderate ARDS with a PaO₂/FiO₂ ratio of 143, a chest radiograph showing bilateral pulmonary infiltrates (Figure 1) and no evidence of heart failure confirmed by bedside echocardiogram.

Figure 1. Bilateral pulmonary opacities consistent with moderate ARDS (PaO₂/FiO₂ ratio 143).

Nasal swab was again negative for influenza by polymerase chain reaction (PCR). Leukocyte count was 4.4 x 10⁹/L with lymphopenia (0.22 x 10⁹/L), hemoglobin was 11.7 g/dL, and platelet count was 216 x 10⁹/L. Sodium was 134 mmol/L, creatinine was 1 mg/dL and AST was 142 U/L. He was initiated of high flow nasal oxygen, and vancomycin and oseltamivir were added. Due to the severity of his condition, he was also started on methylprednisolone (125 mg intravenously every 8 hours). After a brief trial of noninvasive ventilation, he was intubated, sedated, paralyzed and placed on a low tidal volume strategy with an initial PEEP of 15 cm H₂O and a FiO₂ of 0.7. A broncho-alveolar lavage, performed post intubation about 16 hours after admission to our facility, showed 35% alveolar macrophages, 8% lymphocytes and 57% neutrophils and was positive for influenza A by PCR; cultures were negative for other organisms. Other tests including HIV, RSV, Mycoplasma, Legionella and urine for Streptococcus antigen were all negative. The patient improved rapidly. He was extubated two days later, and continued on prednisone (40 mg daily) for five more days when he was dismissed home without any need for supplemental oxygen, although the chest radiograph continued to show infiltrates.

Discussion

This case illustrates a patient with delayed diagnosis and treatment of influenza A associated with moderate ARDS who made a rapid and complete recovery with antiviral, antibiotic and adjunctive high dose corticosteroid therapy. 

The diagnosis of influenza A in this case meets all criteria established by Clinical Practice Guidelines of the Infectious Diseases Society of America (4). Rapid influenza testing lack sensitivity and false negative are not infrequent. ARDS is a well-defined complication of influenza infection. While the administration of corticosteroids appeared to temporally co-relate with clinical improvement, a causal link cannot be established definitively. The role of immunosuppression in influenza associated ARDS is very controversial with conflicting evidence from prospective (supportive) and retrospective (against) studies. For example, the combined use of sirolimus and prednisone was associated with significantly improved oxygenation as well as reduced organ dysfunction in mechanically ventilated patients with severe H1N1 respiratory failure (5). On the other hand, retrospective studies have shown increased mortality with the early use of high dose corticosteroids in severe influenza A pneumonia and respiratory failure. Furthermore, corticosteroids are now rarely used in ARDS and only sparingly given in case of refractory septic shock. The immune response to influenza infection depends on the virus, the host and the host response to infection. Host defense against virus infection consists of both innate and adaptive immune responses. An excessive immune response may result in ‘collateral damage’ and critical respiratory illness which may be ameliorated by the use of systemic corticosteroids. On the other hand, suppression of the host immune system may enhance viral replication and prolong critical illness. As a result of these conflicting data, major societies have been unable to firmly recommend for or against corticosteroids therapy in Influenza A associated respiratory failure.

In conclusion, we report on a case of Influenza A with ARDS and rapid improvement on corticosteroids. We have reviewed the current uncertainty surrounding the use of corticosteroids in this setting and leave open the possibility for careful consideration of this adjunctive therapy in other cases. Randomized trials are needed to further delineate the potential benefit of corticosteroids in severe influenza infection.

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Cite as: Bauer PR, Iyer VN. Corticosteroids and influenza A associated acute respiratory distress syndrome. Southwest J Pulm Crit Care. 2016;13(5):248-51. doi: https://doi.org/10.13175/swjpcc102-16 PDF