The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit.

Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC's pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3-16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.

Intra-abdominal hypertension and hypoxic respiratory failure together predict adverse outcome - A sub-analysis of a prospective cohort.

PURPOSE: To assess whether the combination of intra-abdominal hypertension (IAH, intra-abdominal pressure ≥ 12 mmHg) and hypoxic respiratory failure (HRF, PaO2/FiO2 ratio < 300 mmHg) in patients receiving invasive ventilation is an independent risk factor for 90- and 28-day mortality as well as ICU- and ventilation-free days. METHODS: Mechanically ventilated patients who had blood gas analyses performed and intra-abdominal pressure measured, were included from a prospective cohort. Subgroups were defined by the absence (Group 1) or the presence of either IAH (Group 2) or HRF (Group 3) or both (Group 4). Mixed-effects regression analysis was performed. RESULTS: Ninety-day mortality increased from 16% (Group 1, n = 50) to 30% (Group 2, n = 20) and 27% (Group 3, n = 100) to 49% (Group 4, n = 142), log-rank test p < 0.001. The combination of IAH and HRF was associated with increased 90- and 28-day mortality as well as with fewer ICU- and ventilation-free days. The association with 90-day mortality was no longer present after adjustment for independent variables. However, the association with 28-day mortality, ICU- and ventilation-free days persisted after adjusting for independent variables. CONCLUSIONS: In our sub-analysis, the combination of IAH and HRF was not independently associated with 90-day mortality but independently increased the odds of 28-day mortality, and reduced the number of ICU- and ventilation-free days.

Mild to moderate intra-abdominal hypertension: Does it matter?

This review summarizes the epidemiology, pathophysiological consequences and impact on outcome of mild to moderate (Grade I to II) intra-abdominal hypertension (IAH), points out possible pitfalls in available treatment recommendations and focuses on tasks for future research in the field. IAH occurs in about 40% of ICU patients. Whereas the prevalence of abdominal compartment syndrome seems to be decreasing, the prevalence of IAH does not. More than half of IAH patients present with IAH grade I and approximately a quarter with IAH grade II. However, most of the studies have addressed IAH as a yes-or-no variable, with little or no attention to different severity grades. Even mild IAH can have a negative impact on tissue perfusion and microcirculation and be associated with an increased length of stay and duration of mechanical ventilation. However, the impact of IAH and its different grades on mortality is controversial. The influence of intra-abdominal pressure (IAP) on outcome most likely depends on patient and disease characteristics and the concomitant macro- and microcirculation. Therefore, management might differ significantly. Today, clear triggers for interventions in different patient groups with mild to moderate IAH are not defined. Further studies are needed to clarify the clinical importance of mild to moderate IAH identifying clear triggers for interventions to lower the IAP.

Analysis of microcirculation measurements by novice users trained by a standardized interactive tutorial: An inter-observer variability study.

Excessive time for analysis may impede microcirculatory studies with large amounts of video data. Engaging more personnel in the analyses seems to be a rational approach in that scenario and could shorten the time-interval between capturing images and obtaining results. Our hypothesis was that novice users would be able to determine standard microcirculatory parameters using a semi-automated software with an acceptable degree of variability after participating in a standardized interactive training session. 14 volunteers were included in the study. All volunteers analyzed separately the same sample video after the training. The kappa statistic was calculated for the primary outcome parameter microvascular flow index (MFI) within small and large vessels and indicated a fair level of agreement in the results of the novice users. A standardized interactive tutorial can be useful to teach microcirculatory analysis in previously untrained subjects.

Effects of high volume haemodiafiltration on inflammatory response profile and microcirculation in patients with septic shock.

BACKGROUND: High volumes of haemofiltration are used in septic patients to control systemic inflammation and improve patient outcomes. We aimed to clarify if extended intermittent high volume online haemodiafiltration (HVHDF) influences patient haemodynamics and cytokines profile and/or has effect upon sublingual microcirculation in critically ill septic shock patients. METHODS: Main haemodynamic and clinical variables and concentrations of cytokines were evaluated before and after HVHDF in 19 patients with septic shock requiring renal replacement therapy due to acute kidney injury. Sublingual microcirculation was assessed in 9 patients. RESULTS: The mean (SD) time of HVHDF was 9.4 (1.8) hours. The median convective volume was 123 mL/kg/h. The mean (SD) dose of norepinephrine required to maintain mean arterial pressure at the target range of 70-80 mmHg decreased from 0.40 (0.43) µg/kg/min to 0.28 (0.33) µg/kg/min (p = 0.009). No significant changes in the measured cytokines or microcirculatory parameters were observed before and after HVHDF. CONCLUSIONS: The single-centre study suggests that extended HVHDF results in decrease of norepinephrine requirement in patients with septic shock. Haemodynamic improvement was not associated with decrease in circulating cytokine levels, and sublingual microcirculation was well preserved.

Moderate intra-abdominal hypertension leads to anaerobic metabolism in the rectus abdominis muscle tissue of critically ill patients: a prospective observational study.

PURPOSE: We hypothesize that intra-abdominal hypertension (IAH) is associated with the presence of anaerobic metabolism in the abdominal rectus muscle (RAM) tissue of critically ill patients. METHODS: We included 10 adult, critically ill patients with intra-abdominal pressure (IAP) above 12 mmHg. Microdialysis catheters (CMA 60) were inserted into the RAM tissue. The samples were collected up to 72 hours after enrollment. RESULTS: The patients' median (IQR) APACHE II at inclusion was 29 (21-37); 7 patients were in shock. IAP was 14.5 (12.5-17.8) mmHg at baseline and decreased significantly over time, concomitantly with arterial lactate and vasopressors requirements. The tissue lactate-to-pyruvate (L/P) ratio was 49 (36-54) at the beginning of the study and decreased significantly throughout the study. Additionally, the tissue lactate, lactate-to-glucose (L/G) ratio, and glutamate concentrations changed significantly during the study. The correlation analysis showed that lower levels of pyruvate and glycerol were associated with higher MAP and abdominal perfusion pressures (APP) and that higher levels of glutamate were correlated to elevated IAP. CONCLUSIONS: Moderate IAH leads to RAM tissue anaerobic metabolism suggestive for hypoperfusion in critically ill patients. Correlation analysis supports the concept of using APP as the primary endpoint of resuscitation in addition to MAP and IAP.

Sublingual microcirculation in patients with intra-abdominal hypertension: a pilot study in 15 critically ill patients.

PURPOSE: The purpose of the study is to clarify whether increased intra-abdominal pressure (IAP) is associated with sublingual microcirculatory alterations in intensive care patients. METHODS: Fifteen adult, mechanically ventilated patients were included if their IAP was at least 12 mm Hg for at least 12 hours within the first 3 days after admission to the intensive care unit. Sublingual sidestream dark field (SDF) images were recorded twice a day for 7 days. RESULTS: Median (interquartile range) IAP at inclusion was 14.5 (12.5-16.0) mm Hg. The total vascular density of small vessels at the sublingual area was 13.1 (10.6-14.3) per square millimeter at baseline; the proportion of perfused vessels, 78.9% (69.6%-86.2%); and perfused vessels density, 12.4 (10.8-13.8) per square millimeter. The calculated indices suggested relatively good blood flow in the capillaries, with a De Backer score of 9.0 (8.3-10.2) and a microvascular blood flow of 3.0 (2.9-3.0). Blood flow heterogeneity index was 0.3 (0.1-0.5) at study entry. Despite that IAP, vasopressors dose, and arterial lactate decreased significantly over time, no significant changes were observed in sublingual microvascular density or blood flow. Weak correlations of microvascular blood flow (positive) and heterogeneity index (negative) were detected with both mean arterial pressure and abdominal perfusion pressure. CONCLUSIONS: Neither grade I or II intra-abdominal hypertension (IAP from 12 to 18 mm Hg) is associated with significant changes of sublingual microcirculation in intensive care patients. Correlation analysis indicates better microvascular blood flow at higher mean arterial pressure and abdominal perfusion pressure levels.

Sublingual microcirculatory changes during transient intra-abdominal hypertension--a prospective observational study in laparoscopic surgery patients.

BACKGROUND: Microvascular alterations and intra-abdominal hypertension are both involved in development of organ failure. It is not known whether increased intra-abdominal pressure (IAP) is associated with microcirculatory perfusion derangements. HYPOTHESIS: Transient increase in IAP induced by pneumoperitoneum affects sublingual microcirculation. METHODS: 16 laparoscopic cholecystectomy patients were studied. Sidestream dark field (SDF) imaging was used to evaluate sublingual microcirculation. Microcirculatory videos were done before surgery, at least 15 minutes after initiation of pneumoperitoneum and 1 hour after the pneumoperitoneum. Microcirculation cut-off value for vessels was 20 µm. RESULTS: IAP was held at 12.6 (from 12 to 14) mmHg, mean (SD) duration of pneumoperitoneum was 41 (14) minutes. At the baseline, mean total vascular density was 18.8 (2.6) and perfused vessel density 13.2 (2.9) per mm². Proportion of perfused vessels was 59 (11) % and microvascular flow index 2.2 (0.4). Median (IQR) heterogeneity index was 0.6 (0.4-0.9) and mean De Backer score 13.6 (1.5). Increase in IAP did not cause significant changes in sublingual microcirculatory parameters. CONCLUSIONS: Transiently increased IAP due to pneumoperitoneum does not affect sublingual microcirculatory blood flow and vessel density in patients undergoing laparoscopic surgery. However, the low proportion of perfused vessels indicates the prevalence of perioperative microcirculatory deficiency in these patients.

Moderate intra-abdominal hypertension is associated with an increased lactate-pyruvate ratio in the rectus abdominis muscle tissue: a pilot study during laparoscopic surgery.

BACKGROUND: The development of intra-abdominal hypertension [IAH] in critically ill patients admitted to the ICU is an independent predictor of mortality. In an attempt to find an early, clinically relevant metabolic signal of modest IAH, we investigated abdominal wall metabolite concentrations in a small group of patients undergoing laparoscopic surgery. We hypothesized that elevated intra-abdominal pressure [IAP] due to pneumoperitoneum leads to an increased lactate/pyruvate [L/P] ratio in the rectus abdominis muscle [RAM], indicating anaerobic metabolism. METHOD: Six patients scheduled for elective laparoscopic gastric fundoplication were studied. Two hours before surgery, a microdialysis catheter (CMA 60, CMA Small Systems AB, Solna, Sweden) was inserted into the RAM under local anaesthesia. Catheter placement was confirmed by ultrasound. The microdialysis perfusion rate was set at 0.3 µL/min. Dialysate was collected hourly prior to pneumoperitoneum, during pneumoperitoneum, and for 2 h after pneumoperitoneum resolution. IAP was maintained at 12 to 13 mmHg during the surgery. The glucose, glycerol, pyruvate and lactate contents of the dialysate were measured. RESULTS: The median (interquartile range) L/P ratio was 10.3 (7.1 to 15.5) mmol/L at baseline. One hour of pneumoperitoneum increased the L/P ratio to 16.0 (13.6 to 35.3) mmol/L (p = 0.03). The median pneumoperitoneum duration was 86 (77 to 111) min. The L/P ratio at 2 h post-pneumoperitoneum was not different from that at baseline (p = 1.0). No changes in glycerol or glucose levels were observed. CONCLUSIONS: IAH of 12 to 13 mmHg, even for a relatively short duration, is associated with metabolic changes in the abdominal wall muscle tissue of patients undergoing laparoscopic surgery. We suggest that tissue hypoperfusion occurs even during a modest increase in IAP, and intramuscular metabolic monitoring could therefore serve as an early warning sign of deteriorating tissue perfusion.