the incidence of delirium in the intensive care unit ( icu ) ranges from 45% to 87% .
delirium is an independent risk factor for death in the icu , and can result in over sedation , increased duration of mechanical ventilation and increased length of icu stay .
risk factors for delirium include metabolic impairment , substance withdrawal , severe sepsis , drugs like atropine , organophosphorus compound poisoning ( opcp ) and sleep deprivation .
various drugs such as dexmedetomidine , benzodiazepines and antipsychotics have been tried to treat and prevent delirium ; however , these drugs are associated with adverse effects .
the endogenous hormone melatonin is very well known to influence the circadian rhythm , and has effects on sleep quality and cycle which can be used in the management of delirium .
few animal studies have shown the benefit of melatonin in opcp - induced delirium , by reducing oxidative stress and lipid peroxidation of the brain caused by opcp .
hence , this study was conducted with the primary aim of assessing the effect of melatonin on delirium and recovery profile in opcp patients .
this prospective , randomised , double - blind , placebo - controlled study was conducted between september 2014 and december 2015 .
patients aged between 18 and 50 years , presenting with history and clinical syndrome suggestive of organophosphorus compound poisoning ( opcp ) with low pseudocholinesterase levels ( < 5320
iu / l ) were included in the study . acute physiology and chronic health evaluation ii ( apache ii ) scores were assessed at the time of admission and patients whose score was > 20 were excluded .
postcardiac arrest patients , patients on chronic opioids and opioid antagonists , selective serotonin reuptake inhibitors , monoamine oxidase inhibitors , central nervous system depressants , warfarin , angiotensin converting enzyme inhibitors , diuretics , moderate to severe hepatic or renal dysfunction , known psychiatric disorder through history from relatives and patients with history of cardiac disease were excluded from this study .
injection atropine intravenous ( iv ) was administered as 2 mg boluses , till signs of atropinization were achieved ( heart rate > 80 beats / min , systolic blood pressure > 90 mm of hg , drying of oral and tracheobronchial secretions ) and then it was followed by a titrated infusion to maintain heart rate of 80100/min .
injection pralidoxime ( p2am ) iv 30 mg / kg was administered as loading dose , followed by 810 mg / kg / h infusion over 48 h. patients who developed acute respiratory failure due to opcp - induced cholinergic crisis or intermediate syndrome during admission to icu or during the course of stay in icu were intubated and mechanically ventilated . using a computer generated randomisation scheme ,
the drug and the placebo ( same coloured sugar tablets as melatonin ) were removed from their original packs and placed in similar looking sachets numbered as per computer generated random numbers by the nurse not involved in the study .
the details of the sachet number , its contents and the patient receiving it , was maintained by the principal investigator and not revealed to others till the end of the study .
the nurse who administered the drug , the patient who received it and the doctor who observed the findings were all blinded to the contents of the sachet .
group m received tablet melatonin 3 mg , at 9 pm through the ryle 's tube daily from the day of admission and group c received a placebo tablet at the same time in the same manner throughout the duration of icu stay .
delirium was assessed in two steps by confusion assessment method for icu ( cam - icu ) .
the level of consciousness was first assessed using the richmond agitation - sedation scale ( rass ) , ( a 10-point scale ranging from + 4 to 5 ) .
rass score of 0 represents calm and alert patient and scores of 4 , and 5 correspond to coma in whom delirium can not be assessed .
the cam - icu assesses patients for four features of delirium ( 1 ) acute onset of mental status changes or a fluctuating course , ( 2 ) inattention , ( 3 ) disorganised thinking and ( 4 ) altered level of consciousness .
the presence of at least three out of these four features was considered for a diagnosis of delirium .
the level of sedation and delirium were assessed 3 times a day at 9 pm , 8 am and 4 pm daily ( every shift ) , and the patient was diagnosed to have delirium if icu - cam was positive even on one occasion of assessment . in case of agitation or intolerance to mechanical ventilation , ( rass 2 ) , rescue sedation with injection midazolam 1 mg iv and injection fentanyl 30 g iv bolus followed by infusion of a drug solution containing injection midazolam ( 0.4 mg / ml ) and injection fentanyl ( 5 g / ml ) , was given and infusion titrated to maintain the rass scale between 2 and + 1 . in those who were not intubated , injection lorazepam 4 mg iv boluses were used to maintain rass scale between 2 and + 1 .
primary outcome measures were , effect of melatonin on the duration of delirium during icu stay in opcp , overall prevalence of delirium and sedation ( fentanyl and midazolam or lorazepam ) requirement .
the requirement of atropine , number of patients requiring mechanical ventilation , the duration of mechanical ventilation and the total duration of icu stay were secondary outcome measures .
intensive monitoring of heart rate , systolic and diastolic blood pressure , oxygen saturation and electrocardiogram were done throughout the icu stay .
other significant events and side effects such as headache , nausea , vomiting if any were observed . on the basis of an unpublished pilot study conducted in our icu ,
the average duration of delirium in opcp patients was observed to be 8.5  2.5 days .
we hypothesised that melatonin administration would reduce the duration of delirium . to detect a minimum of 25% reduction in duration of delirium ,
assuming normal distribution of values , at least 44 subjects would be required with 80% power and 5% probability of type i error to reject null hypothesis .
percentage of patients with delirium was calculated by keeping number of patients having delirium on numerator with total number of patients assessed for delirium on that day as denominator .
the average of the percentage of delirium over 10 days is depicted as the prevalence of delirium .
doses of atropine , midazolam , lorazepam , fentanyl were categorised as increased , decreased or no change and ventilation requirement as present or absent .
multiple comparisons were performed using analysis of variance test for repeated measurements ( rmanova ) .
paired student 's t - test was used for paired numerical data with normal variance .
time taken to be delirium free was analysed by log - rank ( mantel - cox ) test .
statistical analysis was done using statistical package for social sciences ( spss ) version 21 software ( ibm , north castle , new york ) .
a total of 60 patients were screened for the study but only 56 patients were included for final analysis [ figure 1 ] .
the demographic variables , basal apache ii score and pseudocholinesterase levels were comparable between the two groups .
neither of the patients were intubated nor on vasopressors at admission [ table 1 ] .
consort diagram showing the number of patients included and analysed demographic characteristics the average time taken to be delirium free was 9.05  2.75 days in group c compared to 6  2.92 days in group m. analysis done with log - rank test indicated a significant difference between the two groups ( chi - square = 10.710 , ) ( p = 0.001 ) [ figure 2 ] .
the overall prevalence of delirium in group m ( 50.85% ) was lower compared to group c ( 84.81% ) ( p < 0.001 ) . there was a significant reduction in the prevalence of delirium in group m after day 3 , compared to day 1 ( p < 0.004 ) .
less than 30% of patients in group m had delirium after day 5 compared to > 50% patients in group c which was clinically and statistically significant ( p < 0.001 ) .
meir curve analysis done with log - rank test indicates that the time taken to be delirium free is significantly different in the two groups chi - square = 10.71 , ( p = 0.001 ) .
group c ( represented as group 1 in figure ) took significantly longer time to be delirium free than group m ( represented as group 2 in figure ) ( 9.053 days vs. 6.0 days ) the consumption of fentanyl and midazolam was also lower in group m compared to group c [ table 2 and figure 3a , b ] .
the requirement for lorazepam and atropine was not different between the two groups [ table 2 ] .
comparison of outcome measures between two groups ( a and b ) comparison of average daily requirement of fentanyl ( a ) , midazolam and atropine ( b ) between groups , fentanyl and midazolam requirement was significantly lower in group m after day ( p < 0.05 ) the mean heart rate was lower in group m compared to group c ; however , it was statistically significant only on days 2 , 6 , 7 , 8 , 9 and 10 .
the mean arterial blood pressures were comparable between two groups throughout the period of icu stay [ figure 4 ] .
number of patients requiring mechanical ventilation was 21 ( 56.76% ) in group c as compared to 16 ( 43.24% ) in group m ( p = 0.50 ) .
the mean number of days of ventilation was 5.26  5.52 days in group c as compared to 3.88  3.52 days in group m ( p = 0.26 ) [ table 2 ] . both were not statistically significant
duration of icu stay was 9.36  6.35 days in group c as compared to 7.65  3.58 in group m ( p = 0.21 ) [ table 2 ] which was not statistically significant .
comparison of mean heart rate and mean arterial pressures between groups anova and rmanova tests were used for intergroup and intragroup comparison of drug consumption over first 4 days . atropine ( p = 0.151 ) , lorazepam ( p = 0.708 ) consumption showed no significant difference within or between groups .
fentanyl and midazolam consumption was significantly lower in group m compared to group c. further , stratified analysis using cochrane - mantel - hanzel chi - square test to reduce the effect of confounding variables ( midazolam , fentanyl , apache score ) also showed more delirium free subjects in group m compared to group c ( p = 0.0010 ) .
there was no significant association between the number of patients having delirium and the duration of mechanical ventilation .
there were no side effects observed in any of the patients such as vomiting , headache , rashes and itching following drug administration .
five patients in group c developed sepsis and one patient in group m developed ventilator - associated pneumonia .
three patients required tracheostomy in view of prolonged ventilation of > 10 days in group c as compared to none in group m. there was no mortality in any of the groups during icu stay .
the present study shows that time taken to be delirium free was shorter and prevalence of delirium was lower in opcp patients receiving melatonin .
the requirement of sedation was also reduced . however , there was no difference in the duration of mechanical ventilation and icu stay .
society of critical care medicine recommends that all icu patients should be evaluated for delirium , and it is evaluated by cam - icu .
the cam - icu method was originally validated by ely et al . for assessing delirium and it was further used by other authors later on .
it was found to be highly sensitive and specific , with a high inter - rater reliability , which allows easy and reliable assessment of delirium , even by non - psychiatric physicians and others .
delirium commonly seen in opcp may be due to inhibition of acetylcholinesterase and imbalance between antioxidants and oxidants .
it can also be due to pesticide itself , hypoxia , alcohol , other medical conditions and , atropine at therapeutic doses causes toxicity ( delirium ) .
delirium , sleep deprivation or excessive sedation can interfere with the assessment of patient 's neck muscle weakness and general condition .
this can lead to difficulty in weaning from mechanical ventilation in opcp patients , leading to increased duration of icu stay and an overall increase in the costs .
melatonin is mainly produced in the pineal gland from tryptophan , and acts through multiple receptor sites including opioidergic , benzodiazepinergic , muscarinic , nicotinic and most importantly melatonergic receptors present in the central nervous system and dorsal spinal cord .
the drug melatonin ( 3 mg ) has been approved by drug controller general of india as a sedative for sleep disorder , jet lag and circadian rhythm disorders .
studies with different doses of melatonin on sleep and sedation in critically ill patients was found to be safe . in a study assessing the pharmacokinetic property of the drug , melatonin at a dose of 3 mg , in critically ill patients had satisfactory oral bio - availability and also pharmacological levels were maintained up to 10 h following administration .
studies assessing the effect of melatonin on delirium have shown contrasting results . in a recent study , administration of 0.5 mg oral melatonin in elderly patients at night resulted in a reduction of incidence of delirium , whereas a dose of 3 mg in elderly patients with hip fracture did not reduce the incidence of delirium but reduced the duration of delirium . in the present study , administration of melatonin decreased the duration of delirium and prevalence was reduced from the 3 day significantly .
administration of oral melatonin perioperatively produced clinically relevant anxiolytic , sedative and analgesic - sparing effect in various types of surgeries .
it also reduced tourniquet - related pain and produced analgesia in orthopaedic upper limb surgeries , in the present study , it was observed that melatonin administration decreased the requirement of midazolam and fentanyl .
it has been observed that melatonin added to p2am and atropine in the treatment of acute opcp poisoning increases acetylcholinesterase activity in brain tissue , and shows a beneficial effect on brain injury by decreasing lipid peroxidation and oxidative stress in brain tissue which may explain the beneficial effects observed in our study . in a recent meta - analysis , assessing the influence of delirium on outcome in icu patients , the overall risk ratio for death in patients , severity of illness and the adjusted risk of mortality was high in patients with delirium . in similar analysis , there was increased length of stay and duration of mechanical ventilation in intensive care in patients with delirium .
we did not find any difference in the number of patients requiring mechanical ventilation and duration of mechanical ventilation and icu stay which may be attributed smaller sample size . since the primary aim of this study was to assess the effect of melatonin on the duration of delirium due to opcp and its treatment , we excluded patients with apache score > 20 ( severely ill ) .
there was attrition of data after 4 days , due to shift out of the patients to wards and hence validity of the study is limited .
we could not follow the patients in the wards , and there was data loss on retrospective analysis of their case sheets and hence we are not able to comment about hospital stay or mortality after discharge from icu . however , none of the patients included in the study died during icu stay .
effect of melatonin on sleep quality of these patients could not be commented since sleep quality was not monitored in the present study , which is a major limitation . in this study
, we did not obtain the basal blood levels of melatonin which would have thrown further light on the possible effect of opcp on melatonin and consequently , delirium .
future multicentric studies with larger sample size , sufficiently powered enough to assess the effect of melatonin on the overall outcome of the patient may be required before using this drug on a routine basis .
melatonin when given to organophosphate compound poisoning patients at a dose of 3 mg orally reduces the prevalence and duration of delirium .
 background and aims : organophosphate compound poisoning ( opcp ) is associated with high incidence of delirium . 
 melatonin has been tried in the treatment of delirium and has shown a beneficial effect in opcp . 
 this study was conducted to know the effect of melatonin on duration of delirium and recovery profile in opcp patients.methods:double-blind randomised placebo control trial in which 56 patients of opcp confirmed by history and syndrome of opcp with low plasma pseudocholinesterase , aged > 18 years and weighing between 50 and 100 kg , and acute physiology and chronic health evaluation ii score of < 20 were studied . 
 group m ( n = 26 ) received tablet melatonin 3 mg and group c ( n = 30 ) received placebo tablet at 9 pm , every night throughout the intensive care unit ( icu ) stay . 
 delirium was assessed using the confusion assessment method for icu , thrice a day . 
 sedation was provided with injection midazolam , fentanyl and lorazepam . 
 duration of mechanical ventilation , vital parameters , icu stay , sedative and atropine requirement , were recorded.results:the time taken to be delirium free was significantly lower in group m ( 6  2.92 days ) compared to group c ( 9.05  2.75 days ) ( p = 0.001 ) and prevalence of delirium was significantly decreased in group m compared to group c from day 3 onwards . 
 the requirement of midazolam ( group m - 2.98  4.99 mg / day , group c - 9.68  9.17 mg / day , p < 0.001 ) and fentanyl ( group m - 94.09  170.05 g / day , group c - 189.33  156.38 g / day , p = 0.03 ) decreased significantly in group m. there was no significant difference in the average atropine consumption ( p = 0.27 ) , duration of mechanical ventilation ( p = 0.26 ) , icu stay ( p = 0.21 ) and the number of patients requiring mechanical ventilation ( p = 0.50).conclusion : orally given melatonin in organophosphate compound poisoning patients reduces the duration of delirium and the requirement of sedation and analgesia . 