Ornella Piazza

Sepsis associated encephalopathy studied by MRI and cerebral spinal fluid S100B measurement.

The pathogenesis of sepsis associated encephalopathy (SAE) is not yet clear: the blood–brain barrier (BBB) disruption has been indicated among the possible causative mechanisms. S100B, a calcium binding protein, originates in the central nervous system but it can be also produced by extra-cerebral sources; it is passively released from damaged glial cells and neurons; it has limited passage through the BBB. We aimed to demonstrate BBB damage as part of the pathogenesis of SAE by cerebral spinal fluid (CSF) and serum S100B measurements and by magnetic resonance imaging (MRI). This paper describes four septic patients in whom SAE was clinically evident, who underwent MRI and S100B measurement. We have not found any evidence of CSF-S100B increase. Serum S100B increase was found in three out of four patients. MRI did not identify images attributable to BBB disruption but vasogenic edema, probably caused by an alteration of autoregulation, was diagnosed. S100B does not increase in CSF of septic patients; S100B increase in serum may be due to extracerebral sources and does not prove any injury of BBB. MRI can exclude other cerebral pathologies causing brain dysfunction but is not specific of SAE. BBB damage may be numbered among the contributors of SAE, which aetiology is certainly multifactorial: an interplay between the toxic mediators involved in sepsis and the indirect effects of hyperthermia, hypossia and hypoperfusion.

Thrombin antithrombin complex and IL-18 serum levels in stroke patients

The complex picture of inflammation and coagulation alterations comes to life in acute stroke phases. Increasing evidence points to a strong interaction and extensive crosstalk between the inflammation and coagulation systems: the interest towards this relationship has increased since recent experimental research showed that the early administration of antithrombin III (ATIII) decreases the volume of ischemia in mice and might be neuroprotective, playing an antiinflammatory role. We aimed to establish the extent of the relationship among markers of inflammation (S100B and IL-18) and procoagulant and fibrinolytic markers (ATIII, thrombin-antithrombin III complex (TAT), Fibrin Degradation Products (FDP), D-dimer) in 13 comatose patients affected by focal cerebral ischemia. Plasma levels of TAT, D-dimer and FDP, IL18 and S100B were increased. IL-18 and S100B high serum levels in ischemic patients suggest an early activation of the inflammatory cascade in acute ischemic injury. The basic principles of the interaction between inflammatory and coagulation systems are revised, from the perspective that simultaneous modulation of both coagulation and inflammation, rather than specific therapies aimed at one of these systems could be more successful in stroke therapy.

In vitro and ex vivo delivery of tailored siRNA-nanoliposomes for E2F1 silencing as a potential therapy for colorectal cancer

Tailored developed nanoliposomes loaded with a siRNA against the transcription factor E2F1 (siE2F1), were produced and delivered to human colorectal adenocarcinoma cell lines and to intestinal human biopsies. siE2F1 loaded nanoliposomes were produced through a dedicated ultrasound assisted technique producing particles with about 40nm size (Small Unilamellar Vesicles, SUVs) and 100% siRNA encapsulation efficiency. Compared to other production methods, the one proposed here can easily produce particles in the nanometric scale by suitable ultrasonic duty cycle treatments. Furthermore, SUVs have a high degree of size homogeneity, a relevant feature for uniform delivery behaviour. siE2F1-loaded SUVs demonstrated a very low cytotoxicity in cells when compared to a commercial transfection agent. Moreover, SUVs loaded with siE2F1 were effective in the down regulation of the target in cultured colon carcinoma cells and in the consequent reduction of cell growth. Finally, a remarkable uptake and target silencing efficiencies were observed in cultured human biopsy of colonic mucosa. In conclusion, whereas further studies in more complex models are required, the siE2F1-SUVs generated have the potential to contribute to the development of novel effective inflammatory bowel diseases-associated colorectal cancer therapies for a future personalized medicine.

Update on transfusion solutions during surgery: review of hydroxyethyl starches 130/0.4

Objectives Restoration of circulation is crucial in the surgical patient management. Colloids and crystalloids are widely used for blood volume therapy. We reviewed recent trials to evaluate efficacy and safety of hydroxyethyl starch (HES) 130/0.4 during surgery. Material and methods A subjective, not systematic, review of literature was performed. Papers were searched to answer questions about efficacy of HES, its impact on coagulation and inflammation and its effects on pulmonary mechanics and renal function. Conclusions HES 130/0.4 is effective for volume therapy and is less expensive than human albumin. Its effects on coagulation and renal function are manageable; it may ameliorate pulmonary permeability and reduce inflammation.

May soluble form of the receptor for advanced glycation end products be considered a mediator of acute lung injury

To the Editor: We read the article by Jabaudon et al (1) with great interest. The authors suggest that a soluble form of the receptor for advanced glycation end products (sRAGE) could be used as a reliable quantitative biomarker of alveolar epithelial damage during acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) because plasma sRAGE levels were higher in patients with ALI/ARDS than in control subjects, correlated with severity of lung injury, and declined over time, reflecting resolution of the injury to the alveolar epithelial type 1 (AT I) cells. We found that some factors that may affect plasma sRAGE, like trauma, acute renal failure, number of organ failures, and Sequential Organ Failure Assessment score, acute ischemic stroke, body mass index and wast/hip ratio, drugs, ethnic determinants, gene polymorphisms, and red cells transfusions, were not explained or not compared between ALI/ARDS patients and control subjects (2). This may be relevant, because these confounding factors may influence the results and even the decreasing sRAGE plasma levels over time may reflect other pathogenetic changes than resolution of AT I cell injury. The limitations of using sRAGE as an ALI/ARDS biomarker can be also attributable to the observation that, during ALI/ARDS, sRAGE release in biological fluids from AT I cells seems variable, depending not only on ALI/ARDS severity, but also on pathogenetic features linked to ALI/ARDS development as focal/ nonfocal loss of aeration, ventilator parameters, and coexisting pulmonary infections (3). We do agree with the authors that all these variables affecting plasma and bronchoalveolar lavage fluid sRAGE levels in the presence or absence of ALI/ARDS make it difficult to think of cutoff values for the general population and confirm our doubts about the role of sRAGE as an ALI/ARDS diagnostic biomarker (4). At the same time, we share the authors’ interest about the receptor for the advanced glycation end products (RAGE)–RAGE ligands biological axis in ALI/ARDS pathogenesis. In our experience, S100B, a RAGE ligand, stimulated R3/1 cells (AT I-like cells expressing RAGE on the cell surface) to secrete tumor necrosis factorand interleukin-6 in a concentration-dependent manner. sRAGE inhibited S100B-dependent secretion partially, acting as a decoy receptor, but in absence of S100B sRAGE itself stimulated tumor necrosis factor, interleukin-6, and soluble intercellular adhesion molecule-1 secretion. AT I cells may have also proinflammatory functions (5), mediated by activation of RAGE, highly expressed by AT I cells. In this perspective, sRAGE could be considered better a mediator than a marker in ALI/ARDS, but if sRAGE acts as an anti-inflammatory or a proinflammatory mediator is still unclear. Funding provided by the Institutional Italian University Ministry. The authors have not disclosed any potential conflicts of interest.

The use of sugammadex for bariatric surgery: analysis of recovery time from neuromuscular blockade and possible economic impact

Background Neuromuscular block (NMB) monitoring and use of reversal agents accelerate the recovery time and improve the workflow in the operating room. We aimed to compare recovery times after sugammadex or neostigmine administration, and estimate the time spent in operating theater and the possible economic impact of a faster recovery, in morbidly obese patients undergoing bariatric surgery. Methods We conducted a retrospective study that analyzed data from records of morbidly obese patients (body mass index >40 kg/m2) undergoing elective laparoscopic bariatric surgery in which sugammadex or neostigmine were used to reverse NMB. Patients were divided in two groups: group 1 (sugammadex group [SUG]) received rocuronium and sugammadex for reversal and group 2 (neostigmine group [NEO]) received either rocuronium or cisatracurium and neostigmine. Data are presented as mean (standard deviation). Results Compared with NEO, SUG group showed shorter times to achieve train-of-four ratio of 0.9 (P<0.05) and an Aldrete score of 10 (P<0.05), a higher cost (€146.7 vs €3.6 [P<0.05]), plus a remarkable less duration of operating theater occupancy (P<0.05). Sugammadex cost accounted for 2.58% of the total cost per surgery, while neostigmine cost accounted for 0.06%. Total time saved in SUG group was 19.4 hours, which could be used to perform 12 extra laparoscopic sleeve gastrectomies. Conclusion Reversal from NMB was significantly faster with sugammadex than with neostigmine. Although sugammadex was substantially more expensive, duration of operating theater occupancy was reduced with potentially workflow increase or personnel reduced cost.

The effect of liver esterases and temperature on remifentanil degradation in vitro.

Remifentanil is a potent opioid metabolized by serum and tissue esterases; it is routinely administered to patients with liver failure as anaesthetic and analgo-sedative without variation in doses, even if prolonged clinical effects and respiratory depression have been observed in these patients. The aim of this study was to determine remifentanil enzymatic degradation kinetics bearing in mind the effect of liver esterases in order to trace a more accurate pharmacokinetic profile of the drug. Solution samples were taken over time and analysed to measure remifentanil concentration by HPLC. We reproduced the physiological settings, varying temperature and pH in vitro and evaluated the kinetics of degradation of remifentanil in the presence of Rhizopus Oryzae esterases, equine liver esterases and porcine liver esterases. Remifentanil kinetics of degradation was accelerated by porcine liver esterases. Remifentanil in vitro half-life decreases with increasing temperatures in the presence of porcine liver esterases. A drug model simulation considering the effect of temperature in the presence of liver esterases was developed. Remifentanil in vitro half-life decreases with increasing temperatures when porcine liver esterases are present. In this paper we propose a model for describing remifentanil degradation kinetics at various temperatures.

Endogenous Agents That Contribute to Generate or Prevent Ischemic Damage

From single to multicellular organisms, protective mechanisms have evolved against endogenous and exogenous noxious stimuli. Over the past decades numerous signaling pathways by which the brain senses and reacts to such insults as neurotoxins, substrate deprivation and inflammation have been discovered. Research on preconditioning is aimed at understanding endogenous neuroprotection to boost it or to supplement its effectors therapeutically once damage to the brain has occurred, such as after stroke or brain trauma. Another goal of establishing preconditioning protocols is to induce endogenous neuroprotection in anticipation of incipient brain damage. Currently several endogenous neuroprotectants are being investigated in controlled clinical trials. There is consensus that many of the neuroprotectants, which were highly effective in animal models of stroke, but failed in clinical trials, were unsuccessful because of side effects, which in many cases led to premature termination of the trial. Nowadays research aims to overcome this problem by developing compounds which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. In the present review we will give a short overview on the signals, sensors, transducers, and effectors of endogenous neuroprotection. We will first focus on common mechanisms, on which pathways of endogenous neuroprotection converge. We will then discuss various applications of endogenous neuroprotectors and explore the prospects of endogenous neuroprotective therapeutic approaches.

Terlipressin in brain‐death donors

Metabolic management of brain‐death organ donors includes correction of the hormonal perturbations that occur after cerebral death and impair circulatory function. Vasopressin is a hormone secreted by the posterior pituitary gland, which contributes to maintain systemic blood pressure by regulating urine secretion and small arteriole tonus. During brain death, the pituitary gland is damaged and hormone secretion rapidly ceases. Low‐dose vasopressin increases systemic blood pressure and decreases the need for catecholamines in brain‐dead organ donors but it is not available in many countries. Terlipressin is a synthetic analog of vasopressin characterized by greater selectivity for the V1 receptor than vasopressin. To date, the efficacy of terlipressin as a pressor agent in humans has been reported in a few studies.

A complication of a closed-tube endotracheal suction catheter

Endotracheal suctioning is an essential and frequently performed procedure for patients requiring mechanical ventilation. Endotracheal suctioning should guarantee optimal oxygenation and avoidance of accumulation of secretions, leading to tube occlusion, increased work of breathing, atelectasis and pulmonary infections. Yet endotracheal suctioning may also have adverse effects, such as mucosal traumatic lesions, disturbances in cardiac rhythm, microbial contamination of the airway and the environment and hypoxaemia due to interruption of mechanical ventilation. The frequency with which endotracheal suctioning is performed differs with each patient, with reported mean values varying from eight to 17 times per day. Nowadays, two systems are available to perform endotracheal suctioning: the single-use, open suction system (OSS) and the multiple-use, closed suction system (CSS). OSS requires disconnection from the ventilator during endotracheal suctioning, which is not necessary when using CSS. The CSS catheter can remain connected to the patient continuously according to the manufacturer, and thus can be used for multiple endotracheal suctioning procedures, reducing the incidence of airway/ environmental microbial contamination and hypoxaemia due to interruption of positive pressure ventilation [1–4], which can determine, in several clinical conditions, rapid lung de-recruitment (0.6 – 4 s) [5].