Endothelial glycocalyx (EG) is disintegrated during sepsis. We have previously shown that this occurs very early in the course of sepsis and its prevention improves the survival of mice with sepsis. Here, we sought to investigate the possibility of pharmacologically accelerating the restoration of disintegrated EG in sepsis. We used a soilage injection model to induce polymicrobial sepsis in C57/BL6 mice and measured total body EG. En face aortic preparations were used for staining of markers of EG and atomic force microscopy was used to measure EG in vitro. In vitro studies were conducted in cultured endothelial cells either exposed to a lipopolysaccharide or enzymatically denuded of EG. Sulodexide (SDX), a heparin sulfate-like compound resistant to degradation by heparanase, accelerated EG regeneration in vitro and in vivo. The total volume of EG was drastically reduced in septic mice. Administration of SDX produced a dramatic acceleration of EG restoration. This effect, unrelated to any SDX-induced differences in microbial burden, was associated with better control of vascular permeability. Notably, SDX demonstrated not only a remarkable capacity for EG regeneration in vitro and in vivo but was also associated with improved animal survival, even when instituted 2 hours after induction of severe sepsis. In conclusion, 1) EG is disintegrated in sepsis, the event which contributes to high animal mortality; 2) pharmacologic acceleration of EG restoration can be achieved using SDX; and 3) SDX reduces vascular permeability, which is elevated in septic mice, and improves animal survival.

BACKGROUND: In this study, we examined the relationship between postoperative cognitive dysfunction (POCD) and intraoperative regional cerebral oxygen saturation (rSO₂) in elderly patients undergoing spinal surgery. METHODS: We enrolled 87 patients older than 65 years. All patients were tested using a battery of cognitive function tests (Korean Mini-Mental State Examination and visuomotor test of Dynamic Lowenstein Occupational Therapy Cognitive Assessment–Geriatric Version) the day before their surgical operation and on the seventh postoperative day. Our threshold for defining POCD for a given patient was a Reliable Change Index score of <−1.96 occurring on 2 tests. RESULTS: POCD was detected in 20 patients (23%) at the seventh postoperative day. Between-patient baseline characteristics, surgical data, and baseline cognitive function were similar for both those who developed POCD and those who did not. A univariate analysis that included age, female sex, education level, presence of diabetes, and duration of intraoperative decline in rSO₂ to a level of <60% of baseline revealed that only diabetes and duration of rSO₂ <60% (odds ratio, 1.01; 95% confidence interval [CI], 1.005–1.010) were found to be risk factors for POCD. After multivariate logistic regression analysis of these 2 variables, only the duration of rSO₂ <60% (odds ratio, 1.006; 95% CI, 1.00–1.01, P = 0.014) remained as an independent risk factor for POCD. The area under the receiver operation characteristic of the duration of rSO₂ <60% was 0.70 (95% CI, 0.57–0.82; P = 0.008). The optimal cutoff value was 157 minutes with a sensitivity of 75% and specificity of 72%. CONCLUSIONS: This study showed that the duration of decline in rSO₂ <60% during lumbar spinal surgery was correlated with the development of POCD at the seventh postoperative day in elderly patients.

In a randomized, double-blind, prospective study, we investigated whether an intraoperative high versus low dose of remifentanil increased postoperative hyperalgesia and whether magnesium can prevent remifentanil-induced hyperalgesia. Ninety patients undergoing thyroidectomy were randomly assigned to 1 of 3 groups. Remifentanil was intraoperatively infused at 0.05 μg/kg/min (group LO) or 0.2 μg/kg/min (groups HI and HM). Patients in group HM received MgSO(4) 30 mg/kg at induction followed by an intraoperative infusion of 10 mg/kg/h. Mechanical pain thresholds on the forearm and periincisional area were assessed by von Frey filament the evening before surgery and postoperatively at 24 and 48 hours. Pain measured on a verbal numerical rating scale (VNRS) (0-10) and additional analgesics were recorded in the postanesthesia care unit postoperatively at 6, 24, and 48 hours. There was a significantly greater decrease in pain threshold on the periincisional area at 24 and 48 hours postoperatively in group HI, as compared with the other 2 groups. The 95% confidence intervals for the mean difference in pain thresholds on the periincisional area at 24 and 48 hours postoperatively were 0.31 to 1.11 and 0.36 to 1.14 for group HI versus group LO, 0.45 to 1.26 and 0.54 to 1.32 for group HI versus group HM (values are log(10) of force in milligrams). The change in pain threshold on the forearm was similar among the groups. Group HI had significantly higher VNRS scores (median [interquartile range], 3 [2-4]) than group LO (2 [1-3] and group HM (2 [1-3]) at 48 hours postoperatively. The 95% confidence intervals for median difference in VNRS score at 48 hours postoperatively were 1 to 2 for group HI versus group LO and 0 to 2 for group HI versus group HM. There were no significant differences in the number of patients who requested rescue analgesics in the postoperative anesthesia care unit and general ward during 48 hours postoperatively among the 3 groups. A relatively high dose of intraoperative remifentanil enhances periincisional hyperalgesia. Intraoperative MgSO(4) prevents remifentanil-induced hyperalgesia. However, hyperalgesia did not reach clinical relevance in terms of postoperative pain or analgesic consumption in patients undergoing thyroidectomy.

We studied respirophasic variation in carotid artery blood flow peak velocity (ΔVpeak-CA) measured by pulsed wave Doppler ultrasound as a predictor of fluid responsiveness in mechanically ventilated patients with coronary artery disease. Forty patients undergoing elective coronary artery bypass surgery were enrolled. Subjects were classified as responders if stroke volume index (SVI) increased ≥15% after volume expansion (6 ml kg⁻¹). The ΔVpeak-CA was calculated as the difference between the maximum and minimum values of peak velocity over a single respiratory cycle, divided by the average. Central venous pressure, pulmonary artery occlusion pressure, pulse pressure variation (PPV), and ΔVpeak-CA were recorded before and after volume expansion. PPV and ΔVpeak-CA correlated significantly with an increase in SVI after volume expansion. Area under the receiver-operator characteristic curve (AUROC) of PPV and ΔVpeak-CA were 0.75 [95% confidence interval (CI) 0.59–0.90] and 0.85 (95% CI 0.72–0.97). The optimal cut-off values for fluid responsiveness of PPV and ΔVpeak-CA were 13% (sensitivity and specificity of 0.74 and 0.71) and 11% (sensitivity and specificity of 0.85 and 0.82), respectively. In a subgroup analysis of 17 subjects having pulse pressure hypertension (≥ 60 mm Hg), PPV failed to predict fluid responsiveness (AUROC 0.70, P=0.163), whereas the predictability of ΔVpeak-CA remained unchanged (AUROC 0.90, P=0.006). Doppler assessment of respirophasic ΔVpeak-CA seems to be a highly feasible and reliable method to predict fluid responsiveness in mechanically ventilated patients undergoing coronary revascularization. NCT 01836081.

Dexmedetomidine, an α2 adrenergic receptor agonist, has analgesic, sedative and sympatholytic properties, with a lack of respiratory depression. It is licensed only for intensive care sedation. The objective of this study is to investigate whether intravenous (i.v.) patient-controlled analgesia (PCA) with dexmedetomidine added to a fentanyl-based drug mixture could reduce postoperative nausea and vomiting (PONV) in highly susceptible patients undergoing lumbar spinal surgery. A randomised, double-blinded study. At a tertiary university hospital between September 2012 and September 2013. One hundred and eight patients undergoing level 1 or 2 posterior lumbar spinal fusion who had at least three risk factors for PONV (female, nonsmoker, use of postoperative opioids) were randomised into two groups. Three patients were excluded from analysis and 105 patients completed the study. Patients received either dexmedetomidine 0.5 μg kg⁻¹ i.v. (dexmedetomidine group) or 0.9% normal saline (control group) 30 min before the completion of surgery followed by fentanyl 0.5 μg kg⁻¹ and 4 mg ondansetron. Postoperatively, the PCA (fentanyl 10 μg kg⁻¹ with 120 mg ketorolac, with or without dexmedetomidine 10 μg kg⁻¹ made up to a total volume of 100 ml) was programmed to deliver 1 ml bolus (lockout 15 min) with a continuous background infusion of 2 ml h⁻¹. The PCA was used for the first 48 h postoperatively. The incidence and severity of PONV, cumulative dose of PCA fentanyl consumed and pain scores were assessed for 48 h. The dexmedetomidine group experienced less nausea during the time interval 1 to 3 h postoperatively compared with the control group [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.13 to 0.77; P = 0.019]. The intensity of nausea between the groups during the first 48 h was comparable, but the dexmedetomidine group had a lower incidence of moderate to severe nausea (OR 0.28; 95% CI 0.12 to 0.67; P < 0.003). Pain scores were not significantly different between the groups, but patients in the dexmedetomidine group required less fentanyl and less rescue analgesia in the first 12 h. Compared with the control group, patients in the dexmedetomidine group experienced almost twice as many episodes of hypotension and bradycardia, but this failed to reach statistical significance. Adding dexmedetomidine to a fentanyl-based PCA drug mixture reduces the frequency and severity of acute postoperative nausea in highly susceptible patients. Clinicaltrials.gov identifier: NCT01840254.