Faculty Bibliography

There has been a marked increase in the volume of critical care services throughout the world in the last few years with the wide addition of intensive care units in developing nations. Despite extensive efforts in research and some progress in treatment, mortality and morbidity have not significantly decreased. Recent research has demonstrated that modifying standard practices of mechanical ventilation and sedation may contribute to improved patient outcomes. This article discusses how new aspects of physiologically based mechanical ventilation with minimal intravenous sedation may help decrease the incidence of nosocomial pneumonia, modulate systemic inflammatory response, and reduce the incidence of delirium. These interlinked modalities may someday contribute to decreased length of stay and a reduction in treatment-related complications. These concepts may also open new avenues to improve patient care and stimulate ongoing investigation in other areas related to physiologically based critical care practices.

RATIONALE/BACKGROUND:The mitochondrial ATP sensitive potassium channel (mK(ATP)) is implicated in cardioprotection by ischemic preconditioning (IPC), but the molecular identity of the channel remains controversial. The validity of current methods to assay mK(ATP) activity is disputed. OBJECTIVE:We sought to develop novel methods to assay mK(ATP) activity and its regulation. METHODS AND RESULTS/RESULTS:Using a thallium (Tl(+))-sensitive fluorophore, we developed a novel Tl(+) flux based assay for mK(ATP) activity, and used this assay probe several aspects of mK(ATP) function. The following key observations were made. (1) Time-dependent run down of mK(ATP) activity was reversed by phosphatidylinositol-4,5-bisphosphate (PIP(2)). (2) Dose responses of mK(ATP) to nucleotides revealed a UDP EC(50) of approximately 20 micromol/L and an ATP IC(50) of approximately 5 micromol/L. (3) The antidepressant fluoxetine (Prozac) inhibited mK(ATP) (IC(50)=2.4 micromol/L). Fluoxetine also blocked cardioprotection triggered by IPC, but did not block protection triggered by a mK(ATP)-independent stimulus. The related antidepressant zimelidine was without effect on either mK(ATP) or IPC. CONCLUSIONS:The Tl(+) flux mK(ATP) assay was validated by correlation with a classical mK(ATP) channel osmotic swelling assay (R(2)=0.855). The pharmacological profile of mK(ATP) (response to ATP, UDP, PIP(2), and fluoxetine) is consistent with that of an inward rectifying K(+) channel (K(IR)) and is somewhat closer to that of the K(IR)6.2 than the K(IR)6.1 isoform. The effect of fluoxetine on mK(ATP)-dependent cardioprotection has implications for the growing use of antidepressants in patients who may benefit from preconditioning.

PURPOSE OF REVIEW/OBJECTIVE:The purpose of this review is to evaluate new concepts in mechanical ventilation in trauma. We begin with the keystone of physiology prior to embarking on a discussion of several new modes of mechanical ventilation. We will discuss the use of noninvasive ventilation as a mode to prevent intubation and then go on to airway pressure release ventilation, high-frequency oscillatory ventilation, and computer-based, closed loop ventilation. RECENT FINDINGS/RESULTS:The importance of preventing further injury in mechanical ventilation lies at the heart of the introduction of several new strategies of mechanical ventilation. New modes of ventilation have been developed to provide lung recruitment and alveolar stabilization at the lowest possible pressure. SUMMARY/CONCLUSIONS:The old modes of continuous positive airway pressure and bilevel positive airway pressure have been actively introduced in clinical practice in the case of trauma patients. Used with proper pain management protocols, there has been a decrease in the incidence of intubation in blunt thoracic trauma. Airway pressure release ventilation has been gaining a role in the management of thoracic injury and may lead to less incidence of physiologic trauma to mechanically ventilated patients. High-frequency oscillatory ventilation has been shown to be effective in patient care by its ability to open and recruit the lung in trauma patients and in those with acute respiratory distress syndrome but it may not have a role in patients with inhalational injury. Closed loop ventilation is a technology that may better control major pulmonary parameters and lead to more rapid titration from the ventilator to spontaneous breathing.

OBJECTIVES/OBJECTIVE:Hypothermic machine perfusion is a well-established preservation method for kidneys that allows for better preservation over longer periods and pretransplant assessment of graft viability. This technique has only sporadically been used for pancreatic grafts. The aim of this study was to establish a hypothermic machine perfusion model for porcine pancreas perfusion. MATERIALS AND METHODS/METHODS:Fifteen porcine pancreata were subjected to 25 minutes of warm ischemia and 149 minutes of cold ischemia before undergoing meticulous bench work preparation and perfusion, via an aortic segment, on the RM3 perfusion machine with University of Wisconsin (Barr Laboratories Inc., Pomona, NY, USA) solution. Perfusion variables (degrees C, temperature; mm Hg, systolic perfusion pressure; mL/min, flow volume; mm Hg/mL/min, resistance) were recorded every 30 minutes. Tissue samples were assessed for each pancreas preperfusion and postperfusion using a semiquantitative scoring scale to grade histopathologic changes: acinar cell damage (0-4), islet cell damage (0-3), inflammation (0-3), and edema (0-3). RESULTS:Hypothermic machine perfusion time was set at 315 minutes, and all grafts were maintained between 4-10 degrees C. The results were as follows (range, mean -/+ SD): systolic perfusion pressures were 5-13 mm Hg (9.61 -/+ 3.25 mm Hg) during the first 60 minutes (priming), and 15-23 mm Hg (21.07 -/+ 4.26 mm Hg) during the maintenance period. Target flow volumes reached 141-152 mL/min (147.6 -/+ 8.969 mL/min) at 60 pulses per minute. Intrapancreatic resistance decreased throughout priming to 0.03-0.09 mm Hg/mL/min (0.083 -/+ 0.042 mm Hg/mL/min), and remained unchanged until completion of perfusion. Pancreatic weight increase varied from 3.2% to 18.3% (13.36% -/+ 4.961%). There was significant postperfusion reduction in islet and acinar cell damage (P = .001 and P = .01 respectively). CONCLUSIONS:We have developed a model of machine perfusion for porcine pancreata which is simple, reliable, and protects graft histopathologic integrity. The model can be used in further studies to improve the quality of pancreas preservation, and assess and improve the viability of the condition of borderline pancreatic grafts.