Jean Charchaflieh

Perioperative Management of Deep Hypothermic Circulatory Arrest

thermic component significantly decreases brain metabolism and oxygen requirements and thus permits a longer period of interrupted blood perfusion to the brain. The cerebral metabolic rate is related exponentially to brain (core body) temperature, with the cerebral metabolic rate decreasing by about 50% for each 6°C drop in brain temperature.6 Disadvantages of DHCA include increased cardiopulmonary bypass (CPB) time, edema formation, coagulopathy, and alteration in many organ functions including the kidney, the brain, vascular smooth muscles, intestinal mucosa, alveolar epithelium, the liver, and the pancreas. 7,8 Based on reports from 8 major cardiac surgery centers in the United States, Europe, and Japan, the risk of permanent neurologic injury after aortic arch surgery using DHCA ranged from 3% to 12%, renal dysfunction from 5% to 14%, pulmonary insufficiency from 5% to 39%, and left ventricular

The Role of Complement System in Septic Shock

Septic shock is a critical clinical condition with a high mortality rate. A better understanding of the underlying mechanisms is important to develop effective therapies. Basic and clinical studies suggest that activation of complements in the common cascade, for example, complement component 3 (C3) and C5, is involved in the development of septic shock. The involvement of three upstream complement pathways in septic shock is more complicated. Both the classical and alternative pathways appear to be activated in septic shock, but the alternative pathway may be activated earlier than the classical pathway. Activation of these two pathways is essential to clear endotoxin. Recent investigations have shed light on the role of lectin complement pathway in septic shock. Published reports suggest a protective role of mannose-binding lectin (MBL) against sepsis. Our preliminary study of MBL-associated serine protease-2 (MASP-2) in septic shock patients indicated that acute decrease of MASP-2 in the early phase of septic shock might correlate with in-hospital mortality. It is unknown whether excessive activation of these three upstream complement pathways may contribute to the detrimental effects in septic shock. This paper also discusses additional complement-related pathogenic mechanisms and intervention strategies for septic shock.

Localized transmeningeal muscimol prevents neocortical seizures in rats and nonhuman primates: Therapeutic implications

Purpose:  To determine whether muscimol delivered epidurally or into the subarachnoid space can prevent and/or terminate acetylcholine (Ach)–induced focal neocortical seizures at concentrations not affecting behavior and background electroencephalography (EEG) activity.

Increasing ventilator surge capacity in disasters: ventilation of four adult-human-sized sheep on a single ventilator with a modified circuit.

OBJECTIVE Recent manmade and natural disasters have focused attention on the need to provide care to large groups of patients. Clinicians, ethicists, and public health officials have been particularly concerned about mechanical ventilator surge capacity and have suggested stock-piling ventilators, rationing, and providing manual ventilation. These possible solutions are complex and variously limited by legal, monetary, physical, and human capital restraints. We conducted a study to determine if a single mechanical ventilator can adequately ventilate four adult-human-sized sheep for 12h. METHODS We utilized a four-limbed ventilator circuit connected in parallel. Four 70-kg sheep were intubated, sedated, administered neuromuscular blockade and placed on a single ventilator for 12h. The initial ventilator settings were: synchronized intermittent mandatory ventilation with 100% oxygen at 16 breaths/min and tidal volume of 6 ml/kg combined sheep weight. Arterial blood gas, heart rate, and mean arterial pressure measurements were obtained from all four sheep at time zero and at pre-determined times over the course of 12h. RESULTS The ventilator and modified circuit successfully oxygenated and ventilated the four sheep for 12h. All sheep remained hemodynamically stable. CONCLUSION It is possible to ventilate four adult-human-sized sheep on a single ventilator for at least 12h. This technique has the potential to improve disaster preparedness by expanding local ventilator surge capacity until emergency supplies can be delivered from central stockpiles. Further research should be conducted on ventilating individuals with different lung compliances and on potential microbial cross-contamination.

An implantable triple-function device for local drug delivery, cerebrospinal fluid removal and EEG recording in the cranial subdural/subarachnoid space of primates.

Transmeningeal pharmacotherapy for cerebral cortical disorders requires drug delivery through the subdural/subarachnoid space, ideally with a feedback controlled mechanism. We have developed a device suitable for this function. The first novel component of the apparatus is a silicone rubber strip equipped with (a) fluid-exchange ports for both drug delivery and local cerebrospinal fluid (CSF) removal, and (b) EEG recording electrode contacts. This strip can be positioned between the dura and pia maters. The second novel component is an implantable dual minipump that directs fluid movement to and from the silicone strip and is accessible for refilling and emptying the drug and CSF reservoirs, respectively. This minipump is regulated by a battery-powered microcontroller integrating a bi-directional radiofrequency (RF) communication module. The entire apparatus was implanted in 5 macaque monkeys, with the subdural strip positioned over the frontal cortex and the minipump assembly secured to the cranium under a protective cap. The system was successfully tested for up to 8 months for (1) transmeningeal drug delivery using acetylcholine (ACh) and muscimol as test compounds, (2) RF-transmission of neocortical EEG data to assess the efficacy of drug delivery, and (3) local CSF removal for subsequent diagnostic analyses. The device can be used for (a) monitoring neocortical electrophysiology and neurochemistry in freely behaving nonhuman primates for more than 6 months, (b) determining the neurobiological impact of subdural/subarachnoid drug delivery interfaces, (c) obtaining novel neuropharmacological data on the effects of central nervous system (CNS) drugs, and (d) performing translational studies to develop subdural pharmacotherapy devices.

Activated Complement Factors as Disease Markers for Sepsis.

Sepsis is a leading cause of death in the United States and worldwide. Early recognition and effective management are essential for improved outcome. However, early recognition is impeded by lack of clinically utilized biomarkers. Complement factors play important roles in the mechanisms leading to sepsis and can potentially serve as early markers of sepsis and of sepsis severity and outcome. This review provides a synopsis of recent animal and clinical studies of the role of complement factors in sepsis development, together with their potential as disease markers. In addition, new results from our laboratory are presented regarding the involvement of the complement factor, mannose-binding lectin, in septic shock patients. Future clinical studies are needed to obtain the complete profiles of complement factors/their activated products during the course of sepsis development. We anticipate that the results of these studies will lead to a multipanel set of sepsis biomarkers which, along with currently used laboratory tests, will facilitate earlier diagnosis, timely treatment, and improved outcome.

The evolution and current use of invasive hemodynamic monitoring for predicting volume responsiveness during resuscitation, perioperative, and critical care

Traditional hemodynamic monitors such as pulmonary artery and central venous catheters provide continuous data and secure intravenous access, but their diagnostic efficacy has been criticized. Dynamic arterial waveform monitoring is promising, but studies suggest it is reliable only within narrow ventilation and rhythm parameters. Newer algorithm-based hemodynamic monitors have emerged; they, too, are limited in their accuracy and applicability. Intravascular monitors are used to predict fluid responsiveness and need for alternative therapies, such as vasomotor or inotropic support. Recent efficacy data, along with other important clinical findings, are reviewed with regard to invasive monitors. We caution against over-generalizing from existing studies, and provide guidance for clinicians wishing to target monitoring techniques for appropriate patients.

Overexpression of human SOD1 improves survival of mice susceptible to endotoxic shock

Background Protective effects of the antioxidant enzyme Cu-Zn superoxide dismutase (SOD1) against endotoxic shock have not been demonstrated in animal models. We used a murine model to investigate whether overexpression of SOD1 protects against endotoxic shock, and whether the genetic background of SOD1 affects its effective protective effects and susceptibility to endotoxic shock. Methods Transgenic (tg) mice overexpressing human SOD1 and control mice were divided into four groups based on their genetic background: (1) tg mice with mixed genetic background (tg-JAX); (2) wild-type (WT) littermates of tg-JAX strain (WT-JAX); (3) tg mice with C57BL/6J background (tg-TX); (4) WT littermates of tg-TX strain (WT-TX). Activity of SOD1 in the intestine, heart, and liver of tg and control mice was confirmed using a polyacrylamide activity gel. Endotoxic shock was induced by intraperitoneal injection of lipopolysaccharide. Survival rates over 120 hours (mean, 95% confidence interval) were analyzed using Kaplan–Meier survival curves. Results Human SOD1 enzymatic activities were significantly higher in the intestine, heart, and liver of both tg strains (tg-JAX and tg-TX) compared with their WT littermates (WT-JAX and WT-TX, respectively). Interestingly, the endogenous SOD1 activities in tg-JAX mice were decreased compared with their WT littermates (WT-JAX), but such aberrant changes were not observed in tg-TX mice. There was no difference in the survival time between tg-JAX and WT-JAX groups after endotoxic shock (P > 0.05). However, the survival time in the tg-TX group was more than twofold longer than that in the WT-TX group (P < 0.05). In addition, WT-JAX mice survived significantly longer than WT-TX mice (P < 0.05). Conclusion Aberrant decrease of endogenous SOD1 activities may have overshadowed the effect of overexpression of SOD1 in tg mice (tg-JAX). Mice with C57BL/6J background (tg-TX) are more susceptible to lipopolysaccharide-induced endotoxic shock than those with mixed genetic background (tg-JAX). Overexpression of SOD1 is protective only in mice with C57BL/6J background (tg-TX).

Principles of Delivery of Sedatives and Intravenous Anesthetics in Out of Operating Room Anesthesia

Safe and effective delivery of IV sedatives and anesthetics for Out of Operating Room Anesthesia (OORA) is based on the same principles that govern delivery of these medications in the OR settings, while taking into account the unique conditions imposed by the diverse environments of each of the procedural locations. This entails understanding, and implementing, all applicable scientific, technological, regulatory, and organizational principles in order to enhance patient safety and operational efficiency. Delivering OORA poses physical and operational constraints, in the forms of limited lighting; excessive noise; limited access by the clinician to the patient; and limited devise allowance into OORA sites, e.g., MRI suite; disorganized scheduling and inadequate patient preparation.

Perioperative risk stratification of mechanically ventilated critically ill patients: An important first step

In this issue of the Journal of Clinical Anesthesia, Copeland et al. compared the utility of three scoring systems for predicting postoperative survival to discharge in critically ill mechanically-ventilated patients: the American Society of Anesthesiologists (ASA) physical status classification, the Revised Cardiac Risk Index (RCRI), and the Sequential Organ Failure Assessment (SOFA) [1]. Using retrospective data from preoperative assessments and archived clinical data to derive receiver operating curves (ROC), the authors found the value of the area under the curve (AUC) for the ASA classification to be 0.59, for the RCRI 0.60, and for the SOFA score 0.68. The differences in the AUC of the three scores were modest and no score adequately discriminated between survivors and non-survivors. The three scoring systems, which were selected to reflect the different practice patterns of anesthesiologists, internists and intensivists, are different in their scope and purpose. The ASA classification was introduced in 1941 as a five grade scale to subjectively describe the presence and severity of systemic illness and its threat to life, andwas later found to predict perioperative morbidity and mortality [2]. The RCRI is a 1999 revision of the Goldman Cardiac Risk Index, which was introduced in 1977 to calculate the risk of cardiac complications in patients undergoing non-cardiac surgery and used 9 variables to produce a calculated risk between 1% and 78% [3]. Instead, the RCRI uses 6 variables to calculate the risk of cardiacmorbidity andmortality and produces a calculated risk between 0.4% and 11% [4]. The Sepsis-related Organ Failure Assessment (SOFA) scorewas introduced in 1996 as awayof objectively describing the extent of sepsis-associated dysfunction in the six major organ systems of respiratory, nervous, cardiovascular, hepatic, renal and coagulation,with a sum score between 6 and 24 [5]. The same acronym, SOFA, was later used to describe a modification in the name (sequential instead of sepsis-related) and use of the score (all critically ill patients instead of sepsis patients). In 2001, Ferreira et al. found that in mixed medical surgical ICU patients, the highest SOFA score during thefirst 96h had the strongest correlation with ICU mortality, with an AUC of 0.90, followed by the mean SOFA score (0.88), the initial SOFA score (0.79) and the delta-SOFA score (0.76) [6], each of which is greater than the AUC that was found in the current study for perioperative mortality (0.68). This suggests that the slightly better predictive performance of the SOFA score found in the current study reflects better performance of the SOFA score in predicting ICU mortality in general rather than perioperative mortality per se. It is also interesting to note that the subjective ASA classification—which was not designed as a risk stratification tool—performed as well as the more complicated objective RCRI.