Palle Toft

A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial

BACKGROUND Standard treatment of critically ill patients undergoing mechanical ventilation is continuous sedation. Daily interruption of sedation has a beneficial effect, and in the general intesive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation. We aimed to establish whether duration of mechanical ventilation could be reduced with a protocol of no sedation versus daily interruption of sedation. METHODS Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n=70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n=70, control group). Both groups were treated with bolus doses of morphine (2.5 or 5 mg). The primary outcome was the number of days without mechanical ventilation in a 28-day period, and we also recorded the length of stay in the intensive care unit (from admission to 28 days) and in hospital (from admission to 90 days). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00466492. FINDINGS 27 patients died or were successfully extubated within 48 h, and, as per our study design, were excluded from the study and statistical analysis. Patients receiving no sedation had significantly more days without ventilation (n=55; mean 13.8 days, SD 11.0) than did those receiving interrupted sedation (n=58; mean 9.6 days, SD 10.0; mean difference 4.2 days, 95% CI 0.3-8.1; p=0.0191). No sedation was also associated with a shorter stay in the intensive care unit (HR 1.86, 95% CI 1.05-3.23; p=0.0316), and, for the first 30 days studied, in hospital (3.57, 1.52-9.09; p=0.0039), than was interrupted sedation. No difference was recorded in the occurrences of accidental extubations, the need for CT or MRI brain scans, or ventilator-associated pneumonia. Agitated delirium was more frequent in the intervention group than in the control group (n=11, 20%vs n=4, 7%; p=0.0400). INTERPRETATION No sedation of critically ill patients receiving mechanical ventilation is associated with an increase in days without ventilation. A multicentre study is needed to establish whether this effect can be reproduced in other facilities. FUNDING Danish Society of Anesthesiology and Intensive Care Medicine, the Fund of Danielsen, the Fund of Kirsten Jensa la Cour, and the Fund of Holger og Ruth Hess.

Pathophysiology of the systemic inflammatory response after major accidental trauma

BackgroundThe purpose of the present study was to describe the pathophysiology of the systemic inflammatory response after major trauma and the timing of final reconstructive surgery.MethodsAn unsystematic review of the medical literature was performed and articles pertaining to the inflammatory response to trauma were obtained. The literature selected was based on the preference and clinical expertise of authors.DiscussionThe inflammatory response consists of hormonal metabolic and immunological components and the extent correlates with the magnitude of the tissue injury. After trauma and uncomplicated surgery a delicate balance between pro- and anti-inflammatory mediators is observed. Trauma patients are, however, often exposed, not only to the trauma, but to several events in the form of initial surgery and later final reconstructive surgery. In this case immune paralysis associated with increased risk of infection might develop. The inflammatory response is normalized 3 weeks following trauma. It has been proposed that the final reconstructive surgery should be postponed until the inflammatory response is normalized. This statement is however not based on clinical trials.ConclusionPostponement of final reconstructive surgery until the inflammatory is normalized should be based on prospective randomized trials.

Redistribution of lymphocytes after major surgical stress.

Major surgery evokes an endocrine stress response, characterized by increased serum cortisol, plasma adrenaline and noradrenaline. Furthermore, surgical stress is accompanied by lymphopenia and granulocytosis in peripheral blood. The changes in peripheral white blood cells have been demonstrated after surgery asiwell as after cortisol infusion. The aim of the present study was to investigate to which tissueslorgans peripheral blood lymphocytes are redistributed after major surgery. From 20 rabbits lymphocytes were isolated from peripheral blood, labelled with indium‐ 111‐tropolene and reinjected intravenously into the rabbits. Ten of the rabbits underwent major surgery (upper laparatomy) during general anaesthesia, while the control group (n= 10) was anaesthetized without surgery. The endocrine stress response to surgery was measured as serum cortisol, plasma adrenaline and noradrenaline. The redistribution of lymphocytes was imaged with a gamma camera and calculated with a connected computer before, 2, 4 and 7 h after the skin incision. Compared to preoperative values, laparotomy resulted in an increase in serum cortisol from 116.6 to 461.9 nmol/l (mean) and a decrease in the fraction/percentage of lymphocytes in peripheral blood from 43.8% to 14.7% 7 h after surgery. Simultaneously, the activity of the heart and lungs together decreased to 76.1% of initial values, while the spleen activity was unaffected. The radioactivity of the lymphatic tissue increased to 137.8% and 134.7%, respectively, 4 and 7 h after the start of surgery. The results indicate that major surgery induces a redistribution of lymphocytes from peripheral blood to lymphatic tissue. It is suggested that the endocrine stress response may be of major importance.

Prognostic value, kinetics and effect of CVVHDF on serum of the myoglobin and creatine kinase in critically ill patients with rhabdomyolysis.

Background:  (I) To investigate the kinetics of the myoglobin and creatine kinase (CK) in rhabdomyolysis. Especially to describe those patients in whom an isolated increase in the myoglobin or the CK occurred at a later stage. (II) To evaluate the sensitivity of the myoglobin and the CK as prognostic tools for the development of Acute renal failure (ARF). (III) To investigate the effect of continuous venovenous haemodiafiltration (CVVHDF) on the myoglobin elimination in ARF.

The role of cytokines in cardiac surgery

Cytokines are a large and rapidly expanding group of polypeptides produced by many different cell types. Increasing interest has been focused on the role of cytokines as mediators of metabolic, immunological and endocrine responses to surgery. The cytokine response in patients undergoing cardiac surgery during cardiopulmonary bypass (CPB) is fairly well-defined and dominated by the proinflammatory cytokines IL-6, TNF alpha and IL-8 and the antiinflammatory cytokine IL-10. Little is known about the cytokine response in patients who develop postoperative complications but CPB with mechanical trauma and blood contact to artificial membranes is definitely an unphysiological state and may contribute to an uncontrollable response similar to that of patients with multiorgan failure and septic shock.

Long-term psychological effects of a no-sedation protocol in critically ill patients.

IntroductionA protocol of no sedation has been shown to reduce the time patients receive mechanical ventilation and to reduce intensive care and total hospital length of stay. The long-term psychological effects of this strategy have not yet been described. The purpose of the study was to test whether a strategy of no sedation alters long-term psychological outcome compared with a standard strategy with sedation.MethodsDuring intensive care stay, 140 patients requiring mechanical ventilation were randomized to either no sedation or sedation with daily interruption of sedation. This study was done as a single-blinded cohort study. After discharge, patients were interviewed by a neuropsychologist assessing quality of life, depression, anxiety, and posttraumatic stress disorder.ResultsTwo years after randomization, 38 patients were eligible for interview, and 26 patients were interviewed (13 from each group). No difference was found with respect to quality of life (Medical Outcome Study, 36-item short-form health survey). Both mental and physical components were nonsignificant. The Beck depression index was low in both groups (one patient in intervention group versus three patients in the control group were depressed, p = 0.32). Evaluated with the Impact of Events Scale, both groups had low stress scores (one in the intervention group versus two in the control group had scores greater than 32; p = 0.50). State anxiety scores were also low (28 in the control group versus 30 in the intervention group, p = 0.58).ConclusionsOur data suggest that a protocol of no sedation applied to critically ill patients undergoing mechanical ventilation does not increase the risk of long-term psychological sequelae after intensive care compared with standard treatment with sedation.

Effect of Methylprednisolone on the Oxidative Burst Activity, Adhesion Molecules and Clinical Outcome Following Open Heart Surgery

Following cardiac surgery with cardiopulmonary bypass (CPB), activated granulocytes may be involved with ischaemia/ reperfusion injury. The purpose of this study was to investigate whether steroids could reduce the oxidative burst activity of granulocytes, the expression of adhesion molecules on granulocytes and improve clinical outcome. Sixteen patients undergoing open heart surgery participated in the study. Eight were randomized to receive methylprednisolone (30 mg/kg intravenously) at the start of anaesthesia while eight patients served as a control group. The oxidative burst was measured flow cytometrically using 123-dihydrorhodamine. A panel of adhesion molecules was measured using monoclonal antibodies. Following CPB the oxidative burst activity and the expression of the adhesion molecule L-selectin more than doubled compared to initial values. There was no difference between the steroid group and the control group regarding the expression of adhesion molecules or the oxidative burst activity. In the steroid group the fluid gain during extracorporeal circulation (ECC) was 683 ml (median) compared to 1488 ml in the control group. Steroids prevented hyperthermia in the postoperative period but did not improve the weaning from the ventilator or reduce the stay in the intensive-care unit. In conclusion, treatment with steroids prevented hyperthermia following open heart surgery with CPB and reduced capillary leak during ECC. Methylprednisolone, however, did not reduce the oxidative burst activity or the expression of adhesion molecules on granulocytes following CPB.

Enoxaparin, effective dosage for intensive care patients: double-blinded, randomised clinical trial

IntroductionIntensive care unit (ICU) patients are predisposed to thromboembolism. Routine prophylactic anticoagulation is widely recommended. Low-molecular-weight heparins, such as enoxaparin, are increasingly used because of predictable pharmacokinetics. This study aims to determine the subcutaneous (SC) dose of enoxaparin that would give the best anti-factor Xa levels in ICU patients.MethodsThe 72 patients admitted to a mixed ICU at Odense University Hospital (OUH) in Denmark were randomised into four groups to receive 40, 50, 60, or 70 mg SC enoxaparin for a period of 24 hours. Anti-factor Xa activity (aFXa) was measured before, and at 4, 12, and 24 hours after administration. An AFXa level between 0.1 to 0.3 IU/ml was considered evidence of effective antithrombotic activity.ResultsMedian peak (4 hours after administration), aFXa levels increased significantly with an increase in enoxaparin dose, from 0.13 IU/ml at 40 mg, to 0.14 IU/ml at 50 mg, 0.27 IU/ml at 60 mg, and 0.29 IU/ml at 70 mg (P = 0.002). At 12 hours after administration, median aFXa levels were still within therapeutic range for those patients who received 60 mg (P = 0.02).ConclusionsOur study confirmed that a standard dose of 40 mg enoxaparin yielded subtherapeutic levels of aFXa in critically ill patients. Higher doses resulted in better peak aFXa levels, with a ceiling effect observed at 60 mg. The present study seems to suggest inadequate dosage as one of the possible mechanisms for the higher failure rate of enoxaparin in ICU patients.Trial RegistrationISRCTN03037804

Optimising stroke volume and oxygen delivery in abdominal aortic surgery: a randomised controlled trial

Post‐operative complications after open elective abdominal aortic surgery are common, and individualised goal‐directed therapy may improve outcome in high‐risk surgery. We hypothesised that individualised goal‐directed therapy, targeting stroke volume and oxygen delivery, can reduce complications and minimise length of stay in intensive care unit and hospital following open elective abdominal aortic surgery.

Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets

Mitochondrial dysfunction is an important factor contributing to tissue damage in both severe traumatic brain injury and ischemic stroke. This experimental study explores the possibility to diagnose the condition bedside by utilising intracerebral microdialysis and analysis of chemical variables related to energy metabolism.