Table 2 Circadian disruption in critically ill patients: clinical studies

Tweedie et al. [45]

Retrospective study for characterizing core body temperature (CBT) 24-h profiles of 15 ICU patients

80% of all patient days had a significant circadian rhythm with erratic acrophases and normal amplitudes

Nuttall et al. [46]

Retrospective study assessing clinical significance of circadian rhythms in patients with (≤17) and without (n = 120) ICU psychosis, by comparing for 24 h the time of both temperature and urine output nadir

Both groups had altered circadian rhythms, and although all ‘patient days’ had a significant rhythm, 83% of those days had abnormal cosinor-derived parameters

Olofsson et al. [47]

Study of melatonin levels in both blood and urine in 8 critically ill patients under sedation and mechanical ventilation

The circadian rhythm of melatonin release was abolished in all but 1 patient, whereas no correlation was found between melatonin levels and level of sedation

Frisk et al. [48]

Study of 6-SMT and urine cortisol in 16 patients, treated in the ICU of two regional hospitals

Hyposecretion of 6-SMT during mechanical ventilation, increase upon adrenergic stimulation, overall high cortisol excretion and, finally, a disturbed diurnal rhythm of both these hormones in 75% of all patients

Paul and Lemmer [49]

Measurement of CBT every hour and plasma cortisol and melatonin levels every 2 h for 24 h, in 13 sedated ICU patients following surgery or respiratory failure and 11 patients with brain injury

The 24-h circadian profiles of all measured variables were significantly disturbed, with no physiological day-night rhythm in both groups of patients in relation with healthy controls, whereas circadian rhythm alterations were more pronounced in patients with brain injuries

Pina et al. [50]

Prospective analysis of hourly CBT and 4-h interval urine cortisol, melatonin, and 6-SMT profiles in 8 burn patients and 14 controls for 24 h in three sessions, occurring between ICU days 1 to 3, day 10, and days 20 to 30

Circadian rhythms of all measured variables were abolished in all patients in relation with controls. Burn ICU patients displayed significantly higher MESORS of CBT, urine melatonin, 6-SMT, and cortisol compared with the control group, during the three sessions of measurements. 24-h circadian profiles were restored within a 30-day period

Gazendam et al. [51]

Investigation of circadian rhythm disruption in a general ICU population, assessed using CBT profiles over a 48-h period in 21 patients

Acrophase shift in all cases. Acute Physiology and Chronic Health Evaluation (APACHE) III score was predictive of circadian misplacement

Mudlinger et al. [55]

Circadian alterations in 17 septic patients versus 7 non-septic subjects and 21 controls, in the ICU

Urinary 6-SMT exhibited circadian rhythmicity in only 1 of 17 septic patients versus 6 of 7 in non-septic patients and 18 of 23 in normal controls. MESORS appeared slightly increased, phase amplitudes were markedly lower, and acrophase occurred later in septic patients. On the contrary, in both non-septic patients and controls, 6-SMT exhibited a circadian rhythm

Perras et al. [56]

Measurement of single nocturnal melatonin concentration (NMC) in 302 patients during their first night in ICU

Analysis of the whole study population did not reveal any correlation between single melatonin measurement and APACHE II score, but in 14 patients with severe sepsis, an inverse correlation was found

Bagci et al. [57]

Nocturnal plasma melatonin and 6-SMT urine concentrations were measured in 23 septic and 13 non-septic pediatric ICU patients

The NMC during septic shock was increased in relation with no shock states. There was no difference for nocturnal and total 6-SMT excretion between septic patients with and without septic shock and non-septic patients. Nocturnal and total 6-SMT excretion was significantly lower in septic patients with than in septic patient without liver dysfunction. Sedation and mechanical ventilation did not affect melatonin excretion

Gehlbach et al. [58]

Assessment of sleep/wake regulation and circadian rhythmicity for 24 h, through 1-h interval urine measurements of 6-SMT, in 22 mechanically ventilated patients with different diagnoses of ICU admission

The 24-h temporal profile of 6-SMT exhibited a phase delay. There was no difference between patients with and without sepsis and no correlation between APACHE II score and 6-SMT amplitude

Li et al. [59]

11 septic and 11 non-septic patients in ICU. Peripheral blood was drawn at 4-h intervals during the first day of admission

The melatonin secretion acrophase occurred earlier in septic patients compared with non-septic patients. Melatonin MESORS tended to be higher in the septic group. Both Cry-1 and Per-2 expression were decreased, while TNF-α and IL-6 expression were increased in septic patients, reaching a peak at 6:00 p.m, which was consistent with the altered rhythm of melatonin secretion. Suppression of peripheral circadian genes was independent of the melatonin rhythm

Plasma levels of melatonin, TNF-α, IL-6, and messenger RNA levels of circadian genes Cry-1 and Per-2 were analyzed