Fulvio Iscra

Metabolic response to injury and sepsis: changes in protein metabolism

The metabolic response to trauma and sepsis involves an increased loss of body proteins. Specific sites of changes of protein and amino acid metabolism have been identified. In skeletal muscle, the rate of proteolysis is accelerated greatly. The rate of protein synthesis also may be increased but not enough to match the increase in degradation. Intramuscular glutamine concentration is decreased because of increased efflux and possibly decreased de novo synthesis. In the liver, the rate of synthesis of selected proteins (i.e., albumin, transferrin, prealbumin, retinol-binding protein, and fibronectin) is decreased, whereas acute phase protein synthesis is accelerated. Tissues characterized by rapidly replicating cells, such as enterocytes, immune cells, granulation tissue, and keratinocytes, exhibit early alterations in the case of decreased protein synthesis capacity. In these tissues, glutamine use is accelerated. Increased stress hormone (cortisol and glucagon) and cytokine secretion, as well as intracellular glutamine depletion, are potential mediators of altered protein metabolism in trauma and sepsis. However, the relative importance of these factors has not been clarified. Therapy of acute protein catabolism may include the use of biosynthetic human growth hormone, possibly in combination with insulin-like growth factor-1, and the administration of metabolites at pharmacologic doses. We recently studied the effects of carnitine and alanyl-glutamine administration in severely traumatized patients. We found that both carnitine and the glutamine dipeptide restrained whole-body nitrogen loss without affecting selected indices of protein metabolism in the skeletal muscle.

Effects of growth hormone administration on skeletal muscle glutamine metabolism in severely traumatized patients: preliminary report.

We have investigated the effects of 24 h human recombinant growth hormone (hGH) administration on leg muscle glutamine exchange and protein kinetics in severely traumatized patients. Muscle amino acid exchange and protein balance were evaluated using the leg arteriovenous balance technique, whereas changes in skeletal muscle free amino acid concentrations were evaluated in biopsy specimens. hGH infusion decreased phenylalanine release from protein degradation by 56 +/- 14%, and the rate of branched chain amino acid catabolism by 51 +/- 10%. Glutamine release from leg muscle was suppressed by 58 +/- 12%. This latter effect was completely accounted for by a hGH-mediated suppression of glutamine synthesis in skeletal muscle. In conclusion, growth hormone administration in trauma patients may restrain protein and amino acid catabolism in skeletal muscle. However, the growth hormone-mediated suppression of glutamine production we have observed in this study could decrease the systemic availability of this amino acid. During growth hormone treatment, this potential side-effect could be prevented by an exogenous glutamine administration.

Molecular regulation of protein catabolism in trauma patients

In skeletal muscle, protein degradation is accomplished by several proteolytic systems located at different parts of the cell (1,2). In the lysosomes, cathepsin B, D, E, H and L are mainly involved in the degradation of non-myofibrillar proteins such as membrane-associated proteins and endocytosed proteins. In the cytoplasm, the ubiquitin proteasome system degrades the bulk of myofibrillar protein and many other cellular proteins. Proteins to be degraded are covalently bound to multiple ubiquitin molecules by ubiquitinconjugating enzymes, and the degradation of such ubiquitinprotein complex occurs in the proteosome. Calpains m and ~t are also cytoplasmic proteases with unclear functions. Distinct proteolytic enzymes are also located in the mitochondria. Critically ill patients are characterized by accelerated degradation of both myofibrillar and non-myofibrillar muscle proteins. Recent evidence shows that in patients with severe trauma gene expression for cathepsin D, calpain m and critical components of the ubiquitin proteolytic pathway are simultaneously increased in skeletal muscle (3). However, the relative importance and the regulatory mechanisms of the different muscle proteolytic systems after trauma are not completely understood. Molecular control of proteolytic enzymes involves gene transcription, mRNA maturation, mRNA translation and subsequent protein activation (4). The aim of this study was to develop a methodology to simultaneously evaluate in human skeletal muscle gene expression of critical components of different proteolytic systems and their enzymatic activity. We used a competitive polymerase chain reaction (PCR) methodology (5) to accurately quantitate mRNA levels for cathepsin B and ubiquitin in skeletal muscle of severely traumatized patients. Ubiquitin is encoded in the human genome as a multigene family (6). Among the different ubiquitin genes we chose the UbB polyubiquitin gene which codes for three direct repeats of the ubiquitin sequence (6). Enzymatic activity of cathepsin B was also determined in the same muscle specimens.

Recommendations for ulcer prophylaxis in the treatment of patients with severe sepsis and septic shock: a dog chasing its tail?

The guidelines for the treatment of patients with severe sepsis and septic shock, presented in 2004, take into consideration the problem of gastro-protective treatments [1]. The indications provided by this document prompt the use of agents for stress ulcer prophylaxis in all patients with severe sepsis and septic shock [1, 2], and mark this recommendation as gradeA, according to the methodology suggested by Sackett et al. [3]. Treatment with histamine2 (H2) inhibitors, aimed at avoiding gastrointestinal bleeding, is considered “more efficacious than sucralfate”, and a direct comparative study between H2 inhibitors and proton pump inhibitors has never been carried out [1, 2]. Although the authors admit that specific studies on septic patients have never been performed, the literature [4, 5, 6, 7] demonstrates the benefit of prophylaxis on a vast population of critically ill patients, including a number of septic patients [1]. Critical appraisal of all references that represent the evidence for the recommendation made for stress ulcer prophylaxis in patients with severe sepsis and septic shock [1] shows that [4, 5, 6, 7]:

Reply to Dr. Vassallo et al. (ms No. 201807012): Regional Citrate Anticoagulation During Coupled Plasma Filtration and Adsorption May Increase Survival in Septic Shock

Dear Sir, We thank Dr. Vassallo et al. for their interesting observations to our study in which we demonstrated that the outcome of a group of septic shock patients treated with the Coupled Plasma-Filtration and Adsorption (CPFA) was influenced by the volume of plasma processed (Vp), and not by the timing of initiation [1]. Dr. Vassallo et al. argue that the use of regional citrate anticoagulation (RCA) instead of intravenous heparin would increase the running time of the CPFA, and consequently the Vp, which is considered a proxy of the intensity of the treatment. Indeed, Dr. Vassallo’s remark makes sense, considering that previous studies demonstrated (a) a dose-effect relationship between the Vp and the outcome, which is better when this variable exceeds 0.20 L/kg/session [2, 3], and (b) the superiority of RCA over intravenous heparin in patients undergoing renal replacement therapy in terms of duration of the extracorporeal circuit, systemic bleeding and transfusion requirements [4]. Moreover, in septic patients undergoing extracorporeal treatments, finding the right dose of heparin can be challenging due to a number of conditions such as the presence of possible sources of hemorrhage, the low levels of Antithrombin III and the hypercoagulable state determined by the interaction between inflammatory mediators and coagulation factors [5]. For these reasons and a few citrate contraindications, RCA has been recommended even in the absence of an increased risk of bleeding [6]. Our group is well aware of these considerations, but RCA was not yet available in our Department at the time of the study. However, despite the well-known heparin-related shortcomings, we think that its mere replacement with RCA could hardly influence the outcome in septic patients who did not present with increased risk of bleeding. Actually, factors other than clotting can reduce the overall Vp, including the hemodynamic instability, and perhaps more importantly, the interruption of the CPFA due to the need for surgical or diagnostic procedures that cannot be performed at the bedside. In addition, the recent COMPACT II study, which has been prematurely suspended due to an excess mortality rate in the treatment group, required the use of RCA instead of heparin during the CPFA [7, 8].

Influence of Timing of Initiation and Volume of Processed Plasma on the Outcome of Septic Shock Patients Treated with Coupled Plasma Filtration and Adsorption

Background: The extracorporeal removal of mediators is a rescue strategy for septic shock patients, which is still under investigation. Several techniques are available: coupled plasma filtration and adsorption (CPFA) combines plasma processing with renal replacement therapy. Methods: The study aimed to elucidate the role of both timing of initiation and intensity of treatment on the outcome, for which we retrospectively studied 52 patients. We collected the overall pre-CPFA time interval, starting from the first episode of hypotension in the wards and the volume of processed plasma (Vp), which we used as a proxy for intensity of treatment. Results: Timing of initiation did not significantly differ between survivors and non-survivors (25 vs. 27 h), while the Vp did (0.25 vs. 0.17 L/kg/session, p < 0.05). The significance of Vp was confirmed by a multiple logistic regression model. Conclusion: Our study confirms that intensity of CPFA, but not its timing of initiation, correlates with survival of septic shock patients.

Heat stroke: Clinical experience from an Italian ICU during summer 2015

An abnormal peak of mortality attributed to an unusually persisting heat wave (HW) has been recorded throughout Italy by the National Institute of Statistics (ISTAT) during the summer of 2015 [1]. During this time frame a group of patients with an initial diagnosis of severe sepsis or septic shock-related multiple organ dysfunction syndrome (MODS) were admitted to our ICU and treated accordingly; however, the subsequent clinical course indicated the MODS could have been ascribed more appropriately to a classic heat stroke (cHS). Regardless of the cause(s), any sustained increase of the body temperature (BT) not matched by a concomitant heat loss can set the stage for the occurrence of cHS; the responsible mechanisms of both sepsis and cHS are similar and include the production and release of a number of pro-inflammatory cytokines in association with the activation of leukocytes and of the coagulative cascade [2]. Despite these similitudes, the distinction between sepsis and cHS is of paramount importance as the therapeutic approaches of these conditionsdiffer substantially:whereas the prompt administration of broad-spectrum and not the abatement of fever is the cornerstone of the treatment of sepsis, in patients with cHS the rapid cooling of patients represents the main therapeutic goal [2]. Overall, eight patients (4 M and 4 F, age 76 years, IQR 49–81 years) were diagnosed suffering from cHS in the considered period (Table 1). According to the information obtained from the next of kins, no patient