Myocardial blood flow under general anaesthesia with sevoflurane in type 2 diabetic patients: a pilot study

BACKGROUND: In type 2 diabetic patients, cardiac events in the perioperative period may be associated with diminished myocardial vasomotor function and endothelial dysfunction. The influence of sevoflurane anaesthesia on myocardial endothelial dysfunction in type 2 diabetic mellitus is investigated in this pilot study. METHODS: Six males with type 2 diabetes mellitus and eight healthy controls were included. Using myocardial contrast echocardiography, myocardial blood flow (MBF) was measured at rest, during adenosine-induced hyperaemia (endothelium-independent vasodilation) and after sympathetic stimulation by the cold pressor test (endothelium-dependent vasodilation). Measurements were performed before and after induction of sevoflurane anaesthesia. RESULTS: Sevoflurane anaesthesia decreased resting MBF in diabetics but not in controls (P = 0.03), while baseline MBF did not differ between diabetics and controls. Without anaesthesia, adenosine-induced hyperaemia increased MBF in both groups compared to resting values. Adenosine combined with sevoflurane resulted in a lower hyperaemic MBF in both groups compared to no anaesthesia. Differences in MBF in response to adenosine before and after sevoflurane administration were larger in diabetic patients, however not statistically significant in this pilot group (P = 0.08). Myocardial blood flow parameters after the cold pressor test were not different between groups. CONCLUSION: These pilot data in type 2 diabetic patients show that sevoflurane anaesthesia decreases resting myocardial blood flow compared to healthy controls. Further, we observed a trend towards a lower endothelium-independent vasodilation capacity in diabetic patients under sevoflurane anaesthesia. Endothelium-dependent vasodilation was not affected by sevoflurane in diabetic patients. These data provide preliminary insight into myocardial responses in type 2 diabetic patients under general anaesthesia. TRIAL REGISTRATION: http://www.clinicialtrials.gov, NCT0086680

Dexmedetomidine Clearance Decreases with Increasing Drug Exposure:Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Background: Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. Methods: The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. Results: A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng center dot ml(-1), the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. Conclusions: This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng center dot ml(-1) using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines

Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice

Background: Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it’s biochemical mechanisms and effects on inflammatory reactions. Methods: Mice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured. Results: HPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3rd and 6th hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines. Conclusion: Low-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression

Association between prehospital end-tidal carbon dioxide levels and mortality in patients with suspected severe traumatic brain injury

Purpose: Severe traumatic brain injury is a leading cause of mortality and morbidity, and these patients are frequently intubated in the prehospital setting. Cerebral perfusion and intracranial pressure are influenced by the arterial partial pressure of CO2 and derangements might induce further brain damage. We investigated which lower and upper limits of prehospital end-tidal CO2 levels are associated with increased mortality in patients with severe traumatic brain injury. Methods: The BRAIN-PROTECT study is an observational multicenter study. Patients with severe traumatic brain injury, treated by Dutch Helicopter Emergency Medical Services between February 2012 and December 2017, were included. Follow-up continued for 1 year after inclusion. End-tidal CO2 levels were measured during prehospital care and their association with 30-day mortality was analyzed with multivariable logistic regression. Results: A total of 1776 patients were eligible for analysis. An L-shaped association between end-tidal CO2 levels and 30-day mortality was observed (p = 0.01), with a sharp increase in mortality with values below 35 mmHg. End-tidal CO2 values between 35 and 45 mmHg were associated with better survival rates compared to &lt; 35 mmHg. No association between hypercapnia and mortality was observed. The odds ratio for the association between hypocapnia (&lt; 35 mmHg) and mortality was 1.89 (95% CI 1.53–2.34, p &lt; 0.001) and for hypercapnia (≥ 45 mmHg) 0.83 (0.62–1.11, p = 0.212). Conclusion: A safe zone of 35–45 mmHg for end-tidal CO2 guidance seems reasonable during prehospital care. Particularly, end-tidal partial pressures of less than 35 mmHg were associated with a significantly increased mortality.</p

Epidemiology, Prehospital Characteristics and Outcomes of Severe Traumatic Brain Injury in The Netherlands:The BRAIN-PROTECT Study

Objective: A thorough understanding of the epidemiology, patient characteristics, trauma mechanisms, and current outcomes among patients with severe traumatic brain injury (TBI) is important as it may inform potential strategies to improve prehospital emergency care. The aim of this study is to describe the prehospital epidemiology, characteristics and outcome of (suspected) severe TBI in the Netherlands. Methods: The BRAIN-PROTECT study is a prospective observational study on prehospital management of patients with severe TBI in the Netherlands. The study population comprised all consecutive patients with clinical suspicion of TBI and a prehospital GCS score ≤ 8, who were managed by one of the 4 Helicopter Emergency Medical Services (HEMS). Patients were followed-up in 9 trauma centers until 1 year after injury. Planned sub-analyses were performed for patients with “confirmed” and “isolated” TBI. Results: Data from 2,589 patients, of whom 2,117 (81.8%) were transferred to a participating trauma center, were analyzed. The incidence rate of prehospitally suspected and confirmed severe TBI were 3.2 (95% CI: 3.1;3.4) and 2.7 (95% CI: 2.5;2.8) per 100,000 inhabitants per year, respectively. Median patient age was 46 years, 58.4% were involved in traffic crashes, of which 37.4% were bicycle related. 47.6% presented with an initial GCS of 3. The median time from HEMS dispatch to hospital arrival was 54 minutes. The overall 30-day mortality was 39.0% (95% CI: 36.8;41.2). Conclusion: This article summarizes the prehospital epidemiology, characteristics and outcome of severe TBI in the Netherlands, and highlights areas in which primary prevention and prehospital care can be improved

Effects of inspiratory oxygen concentration on endtidal carbon monoxide concentration

OBJECTIVE: Carbon monoxide (CO) is eliminated mainly via the lungs so that exhaled carbon monoxide concentration reflects endogenous production. In this context, we studied the effects of inspiratory oxygen concentration and endotracheal intubation on endtidal CO concentrations. METHODS: In patients undergoing general anaesthesia, endtidal CO concentrations were measured while breathing room air, oxygen as well as after induction of general anaesthesia and endotracheal intubation. To exclude time-dependent effects, patients were assigned to two groups. Patients in group 1 (n = 20) were preoxygenated for 5 minutes, whereas patients in group 2 (n = 20) were preoxygenated for 10 minutes. We also studied the effects of different inspiratory oxygen concentrations in volunteers (n = 20) breathing room air, 50% and 100% oxygen. RESULTS: Breathing oxygen for 5 minutes increased endtidal carbon monoxide concentrations in all patients (in group 1 from 7.6+/-4.9 to 12.6+/- 5.0 ppm, p 0.05). Endtidal CO values however significantly increased with induction of anaesthesia and endotracheal intubation (in group 1 to 21.5 +/- 6.3 ppm, p 0.05). CONCLUSIONS: Endtidal carbon monoxide levels are influenced by inspiratory oxygen concentrations. Induction of anaesthesia and endotracheal intubation further increases endtidal CO concentrations beyond the effects attributable to preoxygenation alone

Antifibrinolytics in the treatment of traumatic brain injury

Purpose of reviewTraumatic brain injury (TBI) is a leading cause of trauma-related deaths, and pharmacologic interventions to limit intracranial bleeding should improve outcomes. Tranexamic acid reduces mortality in injured patients with major systemic bleeding, but the effects of antifibrinolytic drugs on outcomes after TBI are less clear. We therefore summarize recent evidence to guide clinicians on when (not) to use antifibrinolytic drugs in TBI patients.Recent findingsTranexamic acid is the only antifibrinolytic drug that has been studied in patients with TBI. Several recent studies failed to conclusively demonstrate a benefit on survival or neurologic outcome. A large trial with more than 12 000 patients found no significant effect of tranexamic acid on head-injury related death, all-cause mortality or disability across the overall study population, but observed benefit in patients with mild to moderate TBI. Observational evidence signals potential harm in patients with isolated severe TBI.SummaryGiven that the effect of tranexamic acid likely depends on a variety of factors, it is unlikely that a 'one size fits all' approach of administering antifibrinolytics to all patients will be helpful. Tranexamic acid should be strongly considered in patients with mild to moderate TBI and should be avoided in isolated severe TBI

Benefits and harms of increased inspiratory oxygen concentrations

Purpose of review The topic of perioperative hyperoxia remains controversial, with valid arguments on both the 'pro' and 'con' side. On the 'pro' side, the prevention of surgical site infections was a strong argument, leading to the recommendation of the use of hyperoxia in the guidelines of the Center for Disease Control and the WHO. On the 'con' side, the pathophysiology of hyperoxia has increasingly been acknowledged, in particular the pulmonary side effects and aggravation of ischaemia/reperfusion injuries. Recent findings Some 'pro' articles leading to the Center for Disease Control and WHO guidelines advocating perioperative hyperoxia have been retracted, and the recommendations were downgraded from 'strong' to 'conditional'. At the same time, evidence that supports a tailored, more restrictive use of oxygen, for example, in patients with myocardial infarction or following cardiac arrest, is accumulating. Summary The change in recommendation exemplifies that despite much work performed on the field of hyperoxia recently, evidence on either side of the argument remains weak. Outcome-based research is needed for reaching a definite recommendation