Impact of cumulative fluid balance on the pharmacokinetics of extended infusion meropenem in critically ill patients with sepsis.

BACKGROUND: Meropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy. METHODS: Twenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated. RESULTS: Eleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05). CONCLUSIONS: These findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.

A porcine model of endothelial glycocalyx damage by enzymatic digestion: A pilot study.

BACKGROUND: The endothelial glycocalyx (EG) plays a vital role in the physiology and pathophysiology of human microcirculation. Having relevant EG damage model would be important tool for testing new interventions aiming at EG protection and recovery. We describe the first in vivo EG damage model in pig. OBJECTIVE: To investigate the course of animal EG damage induced by specific enzymes. MATERIAL AND METHODS: Four anesthetized piglets received enzymes: 1g hyaluronidase and 25 IU heparanase I intravenously. Blood and urine samples were collected at baseline and 20/40/60/80/100/120 min for detecting markers of endothelial and EG function. Sublingual microcirculation and EG thickness were assessed by Side-stream Dark Field (SDF) imaging and Perfused Boundary Region (PBR) respectively. EG of the mesentery artery was visualized in fluorescent microscopy. RESULTS: Biochemical marker of EG damage syndecan-1 showed temporary increase with return to baseline and was reflected by PBR values. Albumin levels suggested brief period of capillary leakage (decrease in the serum, increase in the urine) with a trend to normalization. Urine glycosaminoglycans peaked at 120 minutes. Microcirculatory perfusion parameter showed significant alteration. Diffusion parameters were altered with no statistical significance. CONCLUSION: EG damage induced by specific enzymes was reflected by temporary changes of biochemical makers together with alteration of microcirculation and changes in fluorescent microscopy of EG layer. Our results support to further validate presented model of EG damage on a larger number of animals.

Delirium in the intensive care unit.

Delirium in intensive care patients occurs with high prevalence and is associated with increased morbidity and mortality, worse long-term clinical outcome and higher economic costs. The article describes the pathophysiology, risk factors and individual types of delirium in patients in the intensive care. The current concepts of access to patients in intensive care are presented with the aim of early detection, treatment and prevention of delirium development.

Comparison of cold crystalloid and colloid infusions for induction of therapeutic hypothermia in a porcine model of cardiac arrest.

INTRODUCTION: Large-volume cold intravenous infusion of crystalloids has been used for induction of therapeutic hypothermia after cardiac arrest. However, the effectiveness of cold colloids has not been evaluated. Therefore, we performed an experimental study to investigate the cooling effect of cold normal saline compared to colloid solution in a porcine model of ventricular fibrillation. METHODS: Ventricular fibrillation was induced for 15 minutes in 22 anesthetized domestic pigs. After spontaneous circulation was restored, the animals were randomized to receive either 45 ml/kg of 1°C cold normal saline (Group A, 9 animals); or 45 ml/kg of 1°C cold colloid solution (Voluven, 6% hydroxyethyl starch 130/0.4 in 0.9% NaCl) during 20 minutes (Group B, 9 animals); or to undergo no cooling intervention (Group C, 4 animals). Then, the animals were observed for 90 minutes. Cerebral, rectal, intramuscular, pulmonary artery, and subcutaneous fat body temperatures (BT) were recorded. In the mechanical ex-vivo sub study we added a same amount of cold normal saline or colloid into the bath of normal saline and calculated the area under the curve (AUC) for induced temperature changes. RESULTS: Animals treated with cold fluids achieved a significant decrease of BT at all measurement sites, whereas there was a consistent significant spontaneous increase in group C. At the time of completion of infusion, greater decrease in pulmonary artery BT and cerebral BT in group A compared to group B was detected (-2.1 ± 0.3 vs. -1.6 ± 0.2°C, and -1.7 ± 0.4 vs. -1.1 ± 0.3°C, p < 0.05, respectively). AUC analysis of the decrease of cerebral BT revealed a more vigorous cooling effect in group A compared to group B (-91 ± 22 vs. -68 ± 23°C/min, p = 0.046). In the mechanical sub study, AUC analysis of the induced temperature decrease of cooled solution revealed that addition of normal saline led to more intense cooling than colloid solution (-7155 ± 647 vs. -5733 ± 636°C/min, p = 0.008). CONCLUSIONS: Intravenous infusion of cold normal saline resulted in more intense decrease of cerebral and pulmonary artery BT than colloid infusion in this porcine model of cardiac arrest. This difference is at least partially related to the various specific heat capacities of the coolants.

Differential effects of intravenous anesthetics on hepatosplanchnic microcirculation in rats: sidestream dark-field imaging study.

This study aimed to investigate the effects of intravenous anesthetics on hepatosplanchnic microcirculation in laparotomized mechanically ventilated rats using Sidestream Dark-field (SDF) imaging. Thirty male Wistar rats were divided into 5 groups (n = 6 each). All rats were initially anesthetized with 60 mg/kg pentobarbital (i.p.) for instrumentation. This was followed by either ketamine, propofol, thiopental, midazolam or saline+fentanyl (iv bolus over 5 min and then maintenance over 90 min). SDF imaging of the liver and distal ileum microcirculation was performed at the baseline and at t = 5, 35, 65 and 95 min. In propofol group there was increase of functional sinusoidal density (FSD) following induction (+25%, P < 0.05) and maintenance at t = 95 min (+10.3%, P < 0.05), in ketamine and midazolam group decrease of FSD was observed after induction (-20.4%, P < 0.05; -10.1%, P < 0.05) and during maintenance at t = 65 min (-11.6%, P < 0.05; -11.4%, P < 0.05) when compared to baseline. Following induction with propofol functional capillary density (FCD) of ileal longitudinal muscle layer increased (+10.6%, P < 0.05) and returned to baseline values during maintenance. Ketamine and midazolam decreased FCD of longitudinal layer after induction (-24.6%, P < 0.05; -21.1%, P < 0.05) and remained decreased during maintenance at t = 95 min (-10.8%, P < 0.05; -15.5%, P < 0.05). In thiopental and control group, changes in microcirculatory parameters were not significant throughout the study. In conclusion, intravenous anesthetics affect the hepatosplanchnic microcirculation differentially, propofol has shown protective effect on the liver and intestinal microcirculation.

Prolonged hypervolemic hemodilution decreases functional capillary density of ileal mucosa in pigs revealed by sidestream dark-field imaging.

OBJECTIVE: Hemodilution changes the physical properties of blood by reducing its hematocrit and blood viscosity. We tested whether prolonged hypervolemic hemodilution (HHD) impairs functional capillary density (FCD) of ileal mucosa in healthy mechanically-ventilated pigs and if there is any correlation between changes in FCD of ileal and sublingual mucosas during HHD. METHODS: Sixteen domestic female pigs were anesthetized, mechanically-ventilated, and randomly assigned to the HHD (20 ml/(kg∙h) Hartmann's solution for 3 h) or fluid restrictive (5 ml/(kg∙h) Hartmann's solution for 3 h) group. Microcirculations of sublingual and ileal mucosas via ileostomy were visualized using sidestream dark-field (SDF) imaging at baseline conditions (t=0 h) and at selected time intervals of fluid therapy (t=1, 2, and 3 h). RESULTS: A significant decrease of ileal FCD (285 (278-292) cm/cm(2)) in the HHD group was observed after the third hour of HHD when compared to the baseline (360 (350-370) cm/cm(2)) (P<0.01). This trend was not observed in the restrictive group, where the ileal mucosa FCD was significantly higher after the third hour of fluid therapy as compared to the HHD group (P<0.01). No correlation between microhemodynamic parameters obtained from sublingual and ileal mucosas was found throughout the study. CONCLUSIONS: Prolonged HHD established by crystalloid solution significantly decreased ileal villus FCD when compared to restrictive fluid regimen. An inappropriate degree of HHD can be harmful during uncomplicated abdominal surgery.

Preserved cerebral microcirculation in early stages of endotoxemia in mechanically-ventilated rabbits.

The purpose of our study was to evaluate changes of the cerebral microcirculation during the early stages of endotoxemia in mechanically-ventilated rabbits using Sidestream dark-field (SDF) imaging. Images were obtained using SDF imaging from the surface of the brain via craniotomy before and after rapid administration of a high dose of endotoxin or saline (control group). Although endotoxin shock was successfully induced, we have not found any significant alteration of the cerebral microcirculation during the shock. We speculate that either the model of sepsis with a rapid high dose of endotoxin does not reflect the usual progression of septic encephalopathy or some components other than cerebral microcirculatory alteration play a role at the early stage of septic encephalopathy and the cerebral microcirculation is still preserved. Further studies are needed to clarify our findings.

Out-of-hospital cardiac arrest from air embolism during sexual intercourse: case report and review of the literature.

We report the successful resuscitation of a 38-year-old woman in cardiac arrest following heterosexual intercourse 7 days after spontaneous abortion and an instrumental uterine evacuation. The collapse was thought to be due to venous air embolism (VAE). Her survival neurologically intact was attributed to appropriate first aid, pre-hospital and subsequent hospital intensive care. Neither a case of an out-of-hospital air embolism where the patient made a good recovery, nor a case of miscarriage followed by collapse from air embolism has been reported in the literature. Air embolism is a very infrequent cause of out-of-hospital cardiac arrest with a high mortality rate. Predominant causal reasons are severe penetrating neck or thoracic injuries and sexual activities in pregnancy, when air can pass into the damaged veins in the wall of the uterus and lead to total obstruction in the heart. Diagnostics and management techniques for venous air embolism are discussed. Air embolism should be included in the differential diagnosis for all young women in cardiac arrest, particularly when occurring during sexual activity. Instructions in risks of sexual intercourse during pregnancy and the puerperium should become part of pregnant women's education.