Oral melatonin decreases need for sedatives and analgesics in critically ill patients

INTRODUCTION. The analgesic/sedative therapy is necessary notwithstanding presents important side effects. Critically ill frequently present alterations of the circadian rhythm, delirium and agitation episodes with the risk of receiving additional sedation. The dramatically reduced endogenous blood melatonin level (both in the basal levels and in night peaks) could play a role in this context. OBJECTIVES. Reducing the need for sedatives and analgesic drugs by the oral administration of melatonin in high-risk critically ill [1] treated with conscious sedation [2]. METHODS. Double-blind RCT between placebo and Melatonin (3 9 2 mg), administered daily at 8 and 12 p.m. from the third ICU day until discharge. Inclusion criteria: ageC18 years, SAPSII[32 points, expected mechanical ventilation (MV) C4, practicability of gastroenteric tract. All patients were treated according to the local guidelines: propofol or midazolam during the first 48 h, immediate introduction of enteral sedation with hydroxyzine (until 600 mg/die) and supplementary lorazepam (until 16 mg/die) if necessary. Therapy was titrated at least three times a day, in order to obtain a conscious sedation (RASS = 0) as soon as possible. RESULTS. 96 patients enrolled: age 72 [60\u201377] years, SAPS II 41 [34\u201354] points,MV11 [6\u2013 22] days. Diagnosis: 17 pancreatitis, 37 acute lung diseases, 23 acute heart diseases, 19 other. The analgesic/sedative therapy during the first 3 ICU days (clinical stabilization) was not different between groups. Melatonin administration determined: early weaning from sedatives and analgesics (Fig. 1; p = 0.0005); significant decrease in total administered doses of hydroxyzine: 2,700 (100\u20138,050) versus 300 (0\u20132100), p\0.001; BDZP equivalents: 1 (0\u2013105) versus 0 (0\u20138), p\0.001; haloperidol: 0 (0\u201315.9) versus 0 (0\u20133), p\0.001; propofol: 20 (0\u2013980) versus 0 (0\u201340), p\0.001; opiates: 2.5 (0\u201382.5) versus 0 (0\u201320), p\0.001; decrease of pain events (VNR[3): 28.6 versus 23.7%, p\0.001; anxiety (VNR[3): 34.3 versus 29.8%, p\0.001; agitation (longer than 1 h): 34.3 versus 32.2%, p\0.001; decrease in physical restraints use: 41.8 versus 31.1%, p\0.001; higher RASS: 0 [-1\u20130] versus 0 [0\u20130],p = 0.003. CONCLUSIONS. Oral melatonin significantly decreased the need for sedative and analgesic drugs in critically ill high-risk patients treated with awake sedation (Clinicaltrial.gov n NCT00470821). REFERENCES. 1. Iapichino G, et al. Crit Care Med 2006;34:1039\u20131043. 2. Cigada M, et al. J Criti Care 2008;23:349\u201335

Metabolic and endocrine effects of sedative agents

PURPOSE OF REVIEW: To bring to the attention of the clinician the metabolic effects of most common sedatives and analgesics used in critically ill patients. RECENT FINDINGS: Most patients admitted to the intensive care unit require sedation and analgesia to reduce anxiety, agitation, and delirium and provide pain relief. Inappropriate sedation and analgesia techniques can cause harm to the already compromised patient if they do not take into account the metabolic effect they produce. SUMMARY: Metabolically critical illness can be divided in two phases, and acute and a prolonged one. Whereas the acute or hypermetabolic phase is characterized by elevated circulating concentration of catabolic hormones and substrate utilization to provide energy to vital organs, the prolonged or catabolic phase of critical illness is marked by reduced endocrine stimulation and severe loss of body cell mass. The most common analgesic and sedative agents used in the intensive care unit, if used in small or moderate doses, do not interfere significantly with the metabolic milieu; however, prolonged infusions, and in high doses, without adequate monitoring of level of sedation and quality of analgesia, can precipitate morbid events. Further research is needed in the metabolic aspects of analgesia and sedation in the intensive care unit, particularly if a multimodal pharmacologic strategy is used whereby multiple interventions aim at minimizing the risk of overdosing and contributing to attenuation of the stress response associated with critical illness

Stressors in the ICU: different perceptions of patients, relatives and staff members

Introduction The high-risk critically ill are exposed to signifi cant stressors, along with diffi culties in communicating them to relatives and members of the staff . The aim of this study was to compare the perception of stressors as reported by patients (P), relatives (R) and ICU staff members (S). Methods A validated questionnaire [1] was used to quantitatively assess discomforts related to the ICU stay. Items were clustered into categories; higher scores refer to a higher stressfulness. The median (IQR) was calculated for each category. Twenty-eight high-risk critically ill at discharge, 55 relatives 48 hours after admission of their next of kin, and a total of 125 staff members (55 attending physicians, 40 nurses and 30 medical students/specialist trainees) were interviewed. Fifty-six of the staff members were used to keep patients consciously sedated as for local guidelines; the remaining used deeper levels of sedation. Nonparametric tests were used as needed. Results All stressor categories were diff erently reported by the three groups analysed: environmental (S = 17 (15 to 19), R = 15 (13 to 18), P = 10 (8 to 11), P <0.01), relationships (S = 23 (21 to 25), R = 20.5 (17 to 24.5), P = 14 (11 to 17), P <0.01), emotional (S = 25.5 (23 to 28), R = 24 (20 to 26), P = 18 (15 to 22), P <0.01), and physical (S = 35 (31 to 38), R = 33 (26.5 to 37), P = 27 (21 to 30), P <0.01). Among the staff members, nurses overestimated more than attending physicians, while trainees are closer to relatives\u2019 perception (P = 0.03). Staff members used to conscious sedation overestimate less the impact of environmental stressors (P = 0.03). Years of experience (r = 0.24, P = 0.03) and age (r = 0.27, P = 0.01) are related to stressor overestimation among staff members. Conclusion Members of the staff should reconsider their beliefs on patients\u2019 perception of stressors. We argue that such an overestimation may bring inappropriate administration of analgesic and sedative drugs, particularly for nurses and older members of staff . Relatives might be useful intermediaries to have a better insight of patients\u2019 perception

Performance determinants and flexible ICU organisation

We faced some of the most important aspects of the problem of the appropriateness of ICU resources use, that are the relationship between volume of activity and mortality, the analysis of cost-effectiveness in intensive care medicine, and the monitoring of the human resource use in ICU. For this aim three different surveys were utilized: one at European level, the second at country level and, third, a regional survey. After developing a new measure of volume called \u201chigh-risk volume\u201d, we explored the relationship between outcome and volume, founding that such association was very strong (from 3 to 17\u201319% decrease in ICU/hospital mortality every five extra high-risk patients treated per bed per year), and that an occupancy rate larger than 80% was associated with higher mortality. Therefore, patients in all levels of risk are better treated in high-risk volume ICUs with a reasonable occupancy rate. Analysing cost-effectiveness in intensive care medicine using a national case-mix categorized in different diagnostic groups, we identified brain haemorrhage, ALI/ARDS and surgical unscheduled patients as users a high volume of monetary resources less efficiently, while the scheduled abdominal surgery patients admitted to receive intensive care and patients on the ICU for minor organ support made the best use of the fewer resources spent. Finally, we designed a new approach to measure the rate and appropriateness of nursing resource use in ICU on a daily basis. Testing this approach on a group of general non-specialist ICUs, we found that the method was powerful enough to adequately distinguish between \u201cover\u201d and \u201cunder-utilization\u201d and to identify all the theoretical scenarios of nurse/resource utilization

Analgesia and functional outcome after total knee arthroplasty: periarticular infiltration vs continuous femoral nerve block

BACKGROUND: Capacity to ambulate represents an important milestone in the recovery process after total knee arthroplasty (TKA). The purpose of this study was to determine the analgesic effect of two analgesic techniques and their impact on functional walking capacity as a measure of surgical recovery. METHODS: Forty ASA II-III subjects undergoing TKA were enrolled in a randomized, double-blind, single-centre study receiving 48 h postoperative analgesia with either periarticular infiltration of local anaesthetic (Group I) or continuous femoral nerve block (Group F). Breakthrough pain relief was achieved with patient-controlled analgesia (PCA) morphine. The main outcome was postoperative morphine consumption. Early (postoperative days 1-3) and late (6 weeks) functional walking capacity (2 and 6 min walk tests, 2MWT and 6MWT, respectively), degree of physical activity (CHAMPS), health-related quality of life (SF-12), and clinical indicators of knee function (WOMAC, Knee Society evaluation, and range of motion) were measured. RESULTS: Patients in Group F used the PCA less (P=0.02) to achieve adequate analgesia. Postoperative 2MWT was similar in both groups (P=0.27). Six weeks after surgery, recovery of 6MWT, physical activity, and knee function were significantly improved in Group F (P<0.05). Preoperative walking capacity, physical activity and early total walking time were the independent predictors of early recovery. Distance and time spent walking were the predictors of functional walking exercise capacity at 6 weeks after surgery. CONCLUSIONS: Femoral block is associated with lower opioid consumption and a better recovery at 6 weeks than periarticular infiltration. Early postoperative activity measures (2MWT and walking time) were proved to be possible indicators of knee function recovery at 6 weeks after surgery

Platelet mitochondrial dysfunction in critically ill patients: comparison between sepsis and cardiogenic shock

Introduction: Platelet mitochondrial respiratory chain enzymes (that produce energy) are variably inhibited during human sepsis. Whether these changes occur even during other acute critical illness or are associated with impaired platelet aggregation and secretion (that consume energy) is not known. The aims of this study were firstly to compare platelet mitochondrial respiratory chain enzymes activity between patients with sepsis and those with cardiogenic shock, and secondly to study the relationship between platelet mitochondrial respiratory chain enzymes activity and platelet responsiveness to (exogenous) agonists in patients with sepsis. Methods: This was a prospective, observational, case-control study. Platelets were isolated from venous blood of 16 patients with severe sepsis or septic shock (free from antiplatelet drugs) and 16 others with cardiogenic shock, within 48 hours from admission to Intensive Care. Platelet mitochondrial respiratory chain enzymes activity was measured with spectrophotometry and expressed relative to citrate synthase activity, a marker of mitochondrial density. Platelet aggregation and secretion in response to adenosine di-phosphate (ADP), collagen, U46619 and thrombin receptor activating peptide were measured with lumiaggregometry only in patients with sepsis. In total, 16 healthy volunteers acted as controls for both spectrophotometry and lumiaggregometry. Results: Platelets of patients with sepsis or cardiogenic shock similarly had lower mitochondrial nicotinamide adenine dinucleotide dehydrogenase (NADH) (P<0.001), complex I (P=0.006), complex I and III (P<0.001) and complex IV (P<0.001) activity than those of controls. Platelets of patients with sepsis were generally hypo-responsive to exogenous agonists, both in terms of maximal aggregation (P<0.001) and secretion (P<0.05). Lower mitochondrial NADH (R 2 0.36; P<0.001), complex I (R2 0.38; P<0.001), complex I and III (R2 0.27; P=0.002) and complex IV (R2 0.43; P<0.001) activity was associated with lower first wave of aggregation with ADP. Conclusions: Several platelet mitochondrial respiratory chain enzymes are similarly inhibited during human sepsis and cardiogenic shock. In patients with sepsis, mitochondrial dysfunction is associated with general platelet hypo-responsiveness to exogenous agonists

Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients

OBJECTIVE: We investigated whether preventing hyperglycemia in septic patients affected the plasma concentration of asymmetric-dimethylarginine and if this was associated with clinical benefit. DESIGN: A prospective, multicenter, randomized, controlled, clinical study. SETTING: Intensive care units (ICU) in three university hospitals. PATIENTS: A total of 72 patients admitted for severe sepsis or septic shock, who stayed at least 3 days in the ICU. At admission the patients were assigned to receive either tight or conventional glycemic control. INTERVENTIONS: Determination of circulating levels of asymmetric-dimethylarginine, arginine, interleukin-6, C-reactive-protein and tumor-necrosis-factor-alpha. MEASUREMENTS AND RESULTS: Blood was sampled at admission (no differences between groups), and on the 3rd, 6th, 9th, and 12th (T12) days. Sequential organ failure assessment was scored at each sampling time. All the data were analyzed on an intention-to-treat basis. The control and treatment groups received the same energy intake, glycemia (110.4 +/- 17.3 vs. 163.0 +/- 28.9 mg/dL, P < 0.001) and insulin (P = 0.02) supply differed. No differences were found in high plasma levels of asymmetric-dimethylarginine (P = 0.812) at any time during the ICU stay. The clinical course, as indicated by markers of inflammation, average and maximum organ failure score, ICU stay and ICU and 90-day mortality, was the same. CONCLUSIONS: Intensive insulin treatment, while achieving glucose control, did not reduce asymmetric-dimethylarginine in high-risk septic patients fed with no more than 25 kcal/kg per day to limit ventilatory demand and to simplify glucose control. DESCRIPTOR: 45 (SIRS/sepsis: clinical studies)