Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial.

BACKGROUND: Critically ill patients suffer from physiological sleep deprivation and have reduced blood melatonin levels. This study was designed to determine whether nocturnal melatonin supplementation would reduce the need for sedation in patients with critical illness. METHODS: A single-center, double-blind randomized placebo-controlled trial was carried out from July 2007 to December 2009, in a mixed medical-surgical Intensive Care Unit of a University hospital, without any form of external funding. Of 1158 patients admitted to ICU and treated with conscious enteral sedation, 82 critically-ill with mechanical ventilation >48 hours and Simplified Acute Physiology Score II>32 points were randomized 1:1 to receive, at eight p.m. and midnight, melatonin (3+3mg) or placebo, from the third ICU day until ICU discharge. Primary outcome was total amount of enteral hydroxyzine administered. RESULTS: Melatonin treated patients received lower amount of enteral hydroxyzine. Other neurological indicators (amount of some neuroactive drugs, pain, agitation, anxiety, sleep observed by nurses, need for restraints, need for extra sedation, nurse evaluation of sedation adequacy) seemed improved, with reduced cost for neuroactive drugs. Post-traumatic stress disorder prevalence did not differ between groups, nor did ICU or hospital mortality. Study limitations include the differences between groups before intervention, the small sample size, and the single-center observation. CONCLUSION: Long-term enteral melatonin supplementation may result in a decreased need for sedation, with improved neurological indicators and cost reduction. Further multicenter evaluations are required to confirm these results with different sedation protocols.

Aerophagia increases the risk of ventilator-associated pneumonia in critically-ill patients.

BACKGROUND: Gastric residual volume in ventilated critically ill may complicate gut function. Over the years studies suggested to tolerate progressively higher residuals. The relationship between such volumes and the development of ventilator-associated pneumonia (VAP) is still under debate. No reports deal with the relevant anecdotal finding of air in the stomach. Aim of the present study is to test the role of air in the development of VAPs. METHODS: Prospective observational trial in consecutive patients with a predicted length of ICU stay >3 days. The first 8 days of stay were studied. Sedation was targeted to have awake/cooperative patients. Early enteral nutrition was attempted. Gastric content was measured every 4 hours by 60 mL-syringe suction. Upper digestive intolerance (UDI) was defined as >2 consecutive findings of liquid >200 mL, aerophagia was defined as >2 consecutive findings of air >150 mL. RESULTS: Three hundred sixty-four patients enrolled, 43 developed VAP (11.8%). Patients were sedated with enteral (76% total time), intravenous (6%) or both (28%) drugs. Conscious sedation was achieved in 54% of the observations. 326 patients began enteral nutrition during the first 24 hours (1000 kcal median calorie intake). 10% developed UDI, 15% had aerophagia. No association was found between VAP and UDI (P=0.78), while significant association was found between VAP and aerophagia (OR=2.88, P<0.01). A sensitivity analysis, excluding patients admitted with respiratory infection, confirmed the results. CONCLUSION: High volumes of air in the stomach significantly increased the risk of developing VAP, while gastric residual volumes were not associated with the incidence of pneumonia.

Performance assessment of a glucose control protocol in septic patients with an automated intermittent plasma glucose monitoring device.

BACKGROUND & AIMS: The optimal level and modality of glucose control in critically ill patients is still debated. A protocolized approach and the use of nearly-continuous technologies are recommended to manage hyperglycemia, hypoglycemia and glycemic variability. We recently proposed a pato-physiology-based glucose control protocol which takes into account patient glucose/carbohydrate intake and insulin resistance. Aim of the present investigation was to assess the performance of our protocol with an automated intermittent plasma glucose monitoring device (OptiScanner™ 5000). METHODS: OptiScanner™ was used in 6 septic patients, providing glucose measurement every 15' from a side-port of an indwelling central venous catheter. Target level of glucose was 80-150 mg/dL. Insulin infusion and kcal with nutritional support were also recorded. RESULTS: 6 septic patients were studied for 319 h (1277 measurements); 58 [45-65] hours for each patient (measurements/patient: 231 [172-265]). Blood glucose was at target for 93 [90-98]% of study time. Mean plasma glucose was 126 ± 11 mg/dL. Only 3 hypoglycemic episodes (78, 78, 69 mg/dL) were recorded. Glucose variability was limited: plasma glucose coefficient of variation was 11.7 ± 4.0% and plasma glucose standard deviation was 14.3 ± 5.5 mg/dL. CONCLUSIONS: The local glucose control protocol achieved satisfactory glucose control in septic patients along with a high degree of safeness. Automated intermittent plasma glucose monitoring seemed useful to assess the performance of the protocol.

Intensive care of patients requiring open abdomen treatment: a case-series analysis.

BACKGROUND: This retrospective overview examines the management of patients with temporary open abdomen (OA). METHODS: The clinical characteristics and intensive care treatment of 34 consecutive patients with OA (1996-2012) were reviewed. RESULTS: Average age was 61 years, SAPS II score 43, SOFA 8. Two patients had non-contaminated abdomen; 12 had intact gut (only 8 later during stay); 7 repaired gut (only later 4); 13 cutaneous stoma (later 14), and 2 entero-atmospheric fistula (later 8+1 entero-enteral). The median ICU stay was 48 [36-94] days. One quarter of the 2376 ICU-days were classified as severe sepsis/septic shock (antibiotics were given for two thirds of the stay); three quarters were with ventilation; in 95% of days sedatives were given (mainly enterally). Continuous cavity lavage was done in three quarters of days; in 3% of days patients were fasted whereas >20 kcal/kg was given for 74% of days; we fed the gut in 95% of fed-days, in half of them combined with parenteral nutrition. Complications are discussed; mortality was 32.4%, limited to the ICU stay. CONCLUSION: The intensive care of patients with OA is challenging but can achieve better outcomes than expected. Continuous abdominal lavage improves the evacuation of contaminated fluid or debris and, coupled with antiseptics and low antibiotic pressure, reinforces the control of infection. The gut can be used for nutrition (even without gastrointestinal continuity), and long-term light sedation (mainly enteral) with minimal impact on perfusion, ventilation and gut motility.

In vivo conditioning of acid-base equilibrium by crystalloid solutions: an experimental study on pigs.

PURPOSE: Large infusion of crystalloids may induce acid-base alterations according to their strong ion difference ([SID]). We wanted to prove in vivo, at constant PCO(2), that if the [SID] of the infused crystalloid is equal to baseline plasma bicarbonate, the arterial pH remains unchanged, if lower it decreases, and if higher it increases. METHODS: In 12 pigs, anesthetized and mechanically ventilated at PCO(2) ≈40 mmHg, 2.2 l of crystalloids with a [SID] similar to (lactated Ringer's 28.3 mEq/l), lower than (normal saline 0 mEq/l), and greater than (rehydrating III 55 mEq/l) baseline bicarbonate (29.22 ± 2.72 mEq/l) were infused for 120 min in randomized sequence. Four hours of wash-out were allowed between the infusions. Every 30 min up to minute 120 we measured blood gases, plasma electrolytes, urinary volume, pH, and electrolytes. Albumin, hemoglobin, and phosphates were measured at time 0 and 120 min. RESULTS: Lactated Ringer's maintained arterial pH unchanged (from 7.47 ± 0.06 to 7.47 ± 0.03) despite a plasma dilution around 12%. Normal saline caused a reduction in pH (from 7.49 ± 0.03 to 7.42 ± 0.04) and rehydrating III induced an increase in pH (from 7.46 ± 0.05 to 7.49 ± 0.04). The kidney reacted to the infusion, minimizing the acid-base alterations, by increasing/decreasing the urinary anion gap, primarily by changing sodium and chloride concentrations. Lower urine volume after normal saline infusion was possibly due to its greater osmolarity and chloride concentration as compared to the other solutions. CONCLUSIONS: Results support the hypothesis that at constant PCO(2), pH changes are predictable from the difference between the [SID] of the infused solution and baseline plasma bicarbonate concentration.

Use of preoperative visceral echo-color-Doppler in patients candidates to colonic surgery: preliminary report.

AIM: Postsurgical paralytic ileus is by definition an ileal paralysis longer than three days (72 hours) after a surgery on the gastrointestinal tract. At colorectal surgery we have performed on all candidates a visceral echo-color-Doppler to find a potential correlation with cardiovascular risk factors. METHODS: We have tested patients undergone to colorectal surgical resection performed by laparoscopic and laparotomic surgery, looking for their atherosclerosis status using ultrasound scan, postsurgical complication, bowel digestive function, anastomotic leak. We have also analyzed for each case the value of glycemia, azotemia, creatinemia, cholesterolemia, triglyceridemia, leukocytemia, mean cell volume, hemoglobinemia, albuminemia and moreover age, disease, pathology localization, kind of surgery, weight and height, body mass index (BMI), ASA status (American Society of Anesthesiologists, electrocardiographic distortions, nicotine dependency, diabetes mellitus type I and II). RESULTS: The study enrolled 23 patients, 10 male and 13 female. Middle age was 68.65 ± 11.85 years (range 39-90). In the female subgroup mean age was 69.48 years (range 39-90), while in the male subgroup it was 68 years (range 54-81). In 17 cases out of 23 (73.9%) there was a delay in digestive function, of over 72 hours, with a mean time duration of the paralytic ileus of 4.74 ± 1.60 days (range 3-9). Furthermore a statistically significant correlation between albuminemia and hemoglobinemia presurgery values and lower sierical albuminemia presurgery values in patients who were canalized too late (P=0.03; P=0.041) was found. The non-parametrical values analysis sec. Kruskal-Wallis emphasized a significant correlation between the canalization day, the elettrocardiographic evidence of the pathological situation (P=0.023) and the patient's smoking history (0.023). Another significant value was the creatininemia value: lower values of creatininemia were related to a delayed canalization (P=0.035). CONCLUSION: The statistical analysis does not allow to highlight any correlation between the ultrasound diagnosis of atherosclerosis and the delayed canalization.

Use of oxidized and regenerated cellulose in thyroid surgery: a prospective analysis as cause of postoperative hypocalcemia on 485 patients consecutively treated.

AIM: The intraoperative hemorrage determines an higher risk of parathyroid glands lesions, and laryngeal nerve injuries. We have examined if the use of oxidized and regenerated cellulose could be a cause of postoperative hypocalcemia because of the compression on the parathyroid glands or for tissue adhesions METHODS: From June 2009 to December 2010 we have examined 485 patients consecutively treated with total thyroidectomy. The cases examined were divided in two groups on the use of ionized cellulose (group A and B). 24 hours after surgical procedure, all patients were submitted to serum calcium evaluation. The data were analyzed with χ2 test and t-student test; P<0.05 was statistically significant. RESULTS: We have selected 372 cases out of 485 examined. We have registered after 10 hours from surgical procedure a case of hemorrhage with reintervention in group B (no use of cellulose). The cost of ionized cellulose is € 46; we have used this device in 212 cases on 372 patients undergone to total thyroidectomy, with a cost of € 9 752. The mean value of the serum calcium was statistically different between pre- and postoperative evaluation in all cases (P<0.0001) divided both on gender and on the use of hemostatic devices. CONCLUSION: In our experience, there isn't a statistically significant difference on incidence of postoperative hypocalcemia, related to use of ionized and regenerated cellulose on mean surgical time in all patients either treated with traditional surgery or with video-assisted procedure.

The consumption of glucose during ex vivo lung perfusion correlates with lung edema.

INTRODUCTION: Ex vivo lung perfusion (EVLP) has been recently proposed to recondition organs before transplantation from donors with marginal or unacceptable features. The aim of our investigation was to explore glucose consumption during EVLP. MATERIALS AND METHODS: We investigated 8 domestic pigs (mean weight, 21 ± 0.8 kg). After perfusion with Perfadex, retrieval, and back table surgery, we initiated EVLP. The lungs were perfused with Steen solution with added methylprednisolone, cefazoline, and heparin. The blood flow was gradually increased with a target of 40% of the estimated cardiac output (or less if the pulmonary artery pressure was >15 mm Hg), while keeping the left atrial pressure between 3 and 5 mm Hg. The temperature of the perfusate was increased from 25 °C to 37 °C. Once the temperature of the lung outflow was >32 °C, we began gas flow (4 L/min, 5%-8% CO(2) in air) and mechanical ventilation. EVLP parameters and blood gases were measured throughout the experiment; glucose consumption was calculated as (glucose initial-glucose final)/time. The wet to dry ratio was also calculated as an index of lung edema. RESULTS: When stratified by median glucose consumption (0.237 mg/min), high glucose consumers (0.588 ± 0.17) were characterized by worse lung function, as assessed by oxygenation (partial pressure of oxygen/inspiratory fraction of oxygen [PaO(2)/FiO(2)] 326 ± 63 mm Hg vs 218 ± 84; P=.083 low vs high, respectively), and lung edema (wet/dry ratio 6.5 ± 0.7 vs 8.6 ± 0.9; P=.012). Glucose consumption correlated with wet to dry ratio (R(2)=0.663; P=.014). CONCLUSIONS: We found that the worse the lung function, the greater the consumption of glucose during EVLP. This observation suggests the need to explore lung metabolism during EVLP to possibly obtain metrics for evaluation.

Daily monitoring of biomarkers of sepsis in complicated long-term ICU-patients: can it support treatment decisions?

BACKGROUND: Diagnosis/grading of infection and the systemic response to infection may be difficult on admission to the intensive care unit, but it is even more complicated for severely ill patients with long intensive care stays. The ACCP-SCCM criteria are difficult to apply for such patients, and objective, validated biomarkers would be of great use in this setting. METHODS: Long-term (>6 days) critically ill patients in the general ICU of University Hospital were prospectively enrolled in the study. All patients were assessed daily by the attending physician using the ACCP-SCCM classification. C-reactive protein (CRP, mg/dL), procalcitonin (PCT, ng/mL), and interleukin-6 (IL-6, pg/mL) of daily stored sera were measured after each patient's discharge. After discharge, an independent, overall clinical evaluation and an a posteriori ACCP-SCCM classification were chosen as the reference standard for all comparisons. The assessor was aware of the patient's clinical course but was blinded to levels of biomarkers. RESULTS: We studied clinical variables and biomarkers of 26 patients over a total of 592 patient days. The day-by-day ACCP-SCCM classification of the attending physician overestimated the severity of the inflammatory response to infection. The diagnostic discriminative ability of severe-sepsis/septic-shock for PCT was high (ROC area 0.952 [0.931-0.973]) and had a best threshold value of 1.58 (83.7% sensitivity, 94.6 % specificity). IL-6 had better discriminative ability than CRP, but both were worse than PCT. CONCLUSION: PCT > 0.43 ng/mL could add to the clinical propensity for sepsis vs. SIRS not related to infection. Values higher than 1.58 ng/mL may support the bedside clinical diagnosis of severe-sepsis. PCT between 0.5 and 1.0 suggest tight daily monitoring of clinical conditions and re-evaluation of PCT.

Time course of endogenous nitric oxide inhibitors in severe sepsis in humans.

AIM: Asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) are protein breakdown markers; both compete with arginine for cellular transport and both are excreted in urine. Moreover, ADMA is a non-selective inhibitor of nitric oxide (NO) synthase that is metabolized by a specific hydrolase in which the activity during stress remains controversial. While an increase in ADMA is known to be associated with adverse events, little is known about SDMA. We investigated plasma ADMA and SDMA levels during ICU stay to reveal the time course of endogenous NO inhibition in patients with sepsis. METHODS: A post hoc analysis from a prospective random controlled trial conducted in three ICUs was performed to study the pathophysiological pathways of sepsis. ADMA, SDMA, the ratio of ADMA/SDMA (a marker of ADMA catabolism), arginine, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C reactive protein (CRP) were measured on days 1, 3, 6, 9, 12 and at discharge in 72 consecutive severely septic patients. RESULTS: Fasting basal glycemia, creatinine, IL-6, TNF-alpha, CRP, ADMA, and SDMA were higher than normal. The ADMA/SDMA ratio was decreased by 50%, and arginine levels were low. ADMA levels were related to the total Sequential Organ Failure Assessment (SOFA) scores and arginine levels, and inversely related to IL-6 and CRP levels. SDMA levels were related to Simplified Acute Physiologic Scores II (SAPS II), SOFA scores, blood urea, creatinine, and arginine levels. The ADMA/SDMA ratio was inversely related to IL-6 levels. In 58 ICU survivors, creatinine, IL-6, and CRP levels decreased over time; ADMA levels increased, SDMA levels remained stable, and the ADMA/SDMA ratio increased. In 14 non-survivors, creatinine, IL-6, TNF-alpha, CRP, and ADMA levels were stable, whereas the SDMA levels increased and the ADMA/SDMA ratio remained low. In both ICU survivors and non-survivors, the levels on the last ICU day confirmed the data trends. SDMA, but not ADMA, was associated with ICU mortality. CONCLUSION: ADMA catabolism appears to be activated by inflammation; its increase during the advanced septic phase in surviving patients may suggest an endogenous inhibition of NO synthesis during the full-blown septic phase. In severe sepsis, SDMA, but not ADMA, appears to be a marker of alterations in vital functions and mortality.

Non-invasive ventilation outside the Intensive Care Unit for acute respiratory failure.

Non invasive ventilation (NIV) has been shown to be an effective therapy in selected patients with acute respiratory failure. Due to its benefit and relative ease of use, NIV is frequently used. In addition, the shortage and high cost of intensive care beds have prompted the use of NIV outside the intensive care unit. Choosing the right time and type of patient with acute respiratory failure to improve the chances of success with NIV requires an appropriate environment and monitoring. This review presents and discusses the currently available data regarding NIV success outside the intensive care unit, the optimal ventilatory strategy, possible solutions to the mechanical problems and the minimum monitoring required.

Effects of recombinant human activated protein C on the fibrinolytic system of patients undergoing conventional or tight glycemic control.

AIM: Recombinant human activated protein C (rh-APC) and tight glycemic control (TGC) have been shown to reduce mortality in septic patients. Both interventions can reduce the plasma concentration and/or activity of the most powerful suppressor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1). Our aim was to evaluate the effects on the fibrinolytic system after the administration of rh-APC in septic patients undergoing conventional or TGC. METHODS: Posthoc analysis of data was collected from 90 patients with severe sepsis/septic shock, randomized to either conventional or TGC groups. Independent of these treatments, patients with at least two organ dysfunctions simultaneously received rh-APC. Plasma levels of multiple biochemical markers for fibrinolysis, coagulation, and inflammation were determined every day for the 1st week and then on study days 9, 11, 13, 18, 23, and 28. Clinical data and sepsis-related organ failure assessment (SOFA) scores were also recorded. RESULTS: Patients who had received rh-APC exhibited significantly more impairments in fibrinolysis at baseline (PAI-1 activity 49.76 [24.61-71.82] vs 21.92 [6.47-55-83] IU/mL, P=0.03). The reductions in plasma PAI-1 activity over time associated with rh-APC treatment were different according to whether the treatment was administered to patients undergoing conventional or TGC (P=0.01). However, the most prominent reductions were in patients undergoing conventional glycemic control. Significant interactions between the two study interventions were also found for PAI-1 concentration (P<0.001), C-reactive protein (P=0.02), and interleukin-6 levels (P<0.001). CONCLUSIONS: Both rh-APC and TGC appear to improve fibrinolysis in septic patients. The reduction in the impairment of fibrinolysis associated with rh-APC treatment seems greater in patients undergoing conventional glycemic control than in those undergoing TGC.

The Competency-Based Training in Intensive Care Medicine in Europe (CoBaTrICE) Italian collaborative: national results from the Picker survey.

BACKGROUND: The aim of the Competency-Based Training in Intensive Care Medicine in Europe (CoBaTrICE) project is to create an internationally acceptable competency-based training program for specialists in intensive care medicine. The CoBaTrICE Project has performed a survey, in collaboration with the Picker institute, United Kingdom, to identify desirable characteristics of Intensive Care Unit (ICU) specialists, as expressed by patients and their relatives. METHODS: A questionnaire was developed to assess 21 elements of professional competence. Each element was assigned to one of four categories of a Likert scale: 1=essential; 2=very important; 3=not too important; 4=does not matter. The results were dichotomized into essential (score: 1) and not essential (scores: 2-4) categories. Further, the documents were related to three key concepts: "medical skills and competencies", "communication with patients", and "communication with relatives". Questionnaire statements grouped by theme were also ranked for each item using a number: 1=highest rank; 21=lowest rank. Free text responses were also invited. RESULTS: Ten Italian ICUS were enrolled in the study. There were 249 questionnaires completed (18% total return rate). CONCLUSION: Priority in Italy was given to medical skills and competence. Involvement of patients and relatives in decision-making processes were among the items considered least important. Italian families preferred a paternalist approach to the end of life decision-making process.

Metabolic support of the critically ill: 2008 update.

Nutrition support in critically ill patients is not merely simple nutrition, but rather metabolic support. In the last few years, the pharmacological properties of nutrients have been specifically addressed in a new field called pharmaconutrition. This review will offer a deeper insight into this field, focusing on the properties of arginine, glutamine, antioxidants, and omega-3 fatty acids as well as the level of blood glycemia which should be maintained in critically ill patients.