Development of an Administration Guideline of Oral Medicines to Patients with Dysphagia.

Background and Objectives: There is increasing evidence that patients with dysphagia often have limited access to suitable oral dosage forms, especially when administered via an enteral feeding tube (FT). In addition, there is a lack of clear and readily available information from drug manufacturers on how to administer medications to patients with dysphagia. This study aimed to develop a practical guide for healthcare professionals to increase the safe and effective administration of oral medications to patients with dysphagia. Materials and Methods: The data were collected from existing English databases and handbooks available to develop an easy-to-use tabular guideline presenting all relevant information using keywords and short expressions. The working group differentiated 514 formulation types, and the information was collected and added to the guideline separately. In addition, the instructions for the patients taking the medicines orally or via FT were described separately. Results: The guideline consisted of 24 keywords or short expressions developed by the working group and described the instructions to use them. The guideline contained 343 active pharmaceutical ingredients and 19 fixed-dose combinations. Conclusions: Knowledge about proper medication preparation and administration for patients with swallowing difficulties is limited but essential. It is crucial to encourage drug manufacturers to provide this information as a standard to ensure the safe and effective use of medications for all patient groups.

Solid oral medications' suitability for use in enteral feeding tubes.

BACKGROUND: There is a lack of specific data about the efficacy and safety of medications administered via feeding tubes, although there is a general awareness that not all drug formulations are suitable. AIMS AND OBJECTIVES: To overview the current situation with solid medications administered through feeding tubes in the Tartu University Hospital intensive care units. To evaluate the availability of information on the suitability of drug formulations for administration via feeding tubes. DESIGN: This was a descriptive retrospective document analysis study. METHODS: During visits to the intensive care units, medication data for current patients were collected from paper medical charts and nurses. In addition, package information leaflets, summaries of product characteristics, and two practical handbooks were used for evaluating the medicines' suitability for administration via feeding tubes. A request for information was also sent to manufacturers or marketing authorization holders. RESULTS: In 3 months, data were collected from 113 intensive care patients' medical charts. A total of 306 medication administrations via feeding tubes were documented and analysed, 67% of which were solid oral dosage forms. Exactly 91.2% of these were conventional tablets. After the analysis of information availability, 88% of the medications were classified as suitable for administration via feeding tubes, but only 48% had the manufacturer-provided information. CONCLUSION: This study showed that the information about the suitability of formulations administration through a feeding tube is not readily available for almost half of the medications. The manufacturers seem to have the relevant information, but it is not always added to their medications' official information, putting these patients at higher risk for errors. RELEVANCE TO CLINICAL PRACTICE: This study shows that if there is no clear statement about administration through feeding tubes on official manufacturers' information, this should be sought directly from manufacturers or marketing authorization holders, and the data could be incorporated into local guidelines.

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.

Are We Meeting the Current Standards of Consent for Anesthesia? An International Survey of Clinical Practice.

BACKGROUND International application of existing guidelines and recommendations on anesthesia-specific informed consent is limited by differences in healthcare and legal systems. Understanding national and regional variations is necessary to determine future guidelines. MATERIAL AND METHODS Anonymous paper surveys on their practices regarding anesthesia-specific patient informed consent were sent to anesthesiologists in Estonia, Latvia, and Lithuania. RESULTS A total of 233 responses were received, representing 36%, 26%, and 24% of the practicing anesthesiologists in Lithuania, Latvia, and Estonia, respectively. Although 85% of responders in Lithuania reported using separate forms to secure patient informed consent for anesthesia, 54.5% of responders in Estonia and 50% in Latvia reported using joint forms to secure patient informed consent for surgery and anesthesia. Incident rates were understated by 14.2% of responders and overstated by 66.4% (P<0.001), with the latter frequently quoting incident rates that are several to tens of times higher than those published internationally. Physicians obtaining consent in the outpatient setting were more satisfied with the process than those obtaining consent on the day of surgery, with 62.5% and 42.6%, respectively, agreeing that the informed consent forms provided a satisfactory description of complications (P=0.03). Patients were significantly less likely to read consent information when signing forms on the day of surgery than at earlier times (8.5% vs. 67.5%, P<0.001). Only 46.2% of respondents felt legally protected by the current consent process. CONCLUSIONS Anesthesia-specific informed patient consent practices differ significantly in the 3 Baltic states, with these practices often falling short of legal requirements. Efforts should be made to improving information accuracy, patient autonomy, and compliance with existing legal standards.

Pharmacokinetics of doripenem during high volume hemodiafiltration in patients with septic shock.

Pharmacokinetics (PK) of doripenem was determined during high volume hemodiafiltration (HVHDF) in patients with septic shock. A single 500 mg dose of doripenem was administered as a 1 hour infusion during HVHDF to 9 patients. Arterial blood samples were collected before and at 30 or 60 minute intervals over 8 hours (12 samples) after study drug administration. Doripenem concentrations were determined by ultrahigh performance liquid chromatography-tandem mass spectrometry. Population PK analysis and Monte Carlo simulation of 1,000 subjects were performed. The median convective volume of HVHDF was 10.3 L/h and urine output during the sampling period was 70 mL. The population mean total doripenem clearance on HVHDF was 6.82 L/h, volume of distribution of central compartment 10.8 L, and of peripheral compartment 12.1 L. Doses of 500 mg every 8 hours resulted in 88.5% probability of attaining the target of 50% time over MIC for bacteria with MIC = 2 µg/mL at 48 hours, when doubling of MIC during that time was assumed. Significant elimination of doripenem occurs during HVHDF. Doses of 500 mg every 8 hours are necessary for treatment of infections caused by susceptible bacteria during extended HVHDF.

Postoperative complications and mortality after major gastrointestinal surgery.

BACKGROUND AND OBJECTIVE: The incidence of postoperative complications and death is low in the general population, but a subgroup of high-risk patients can be identified amongst whom adverse postoperative outcomes occur more frequently. The present study was undertaken to describe the incidence of postoperative complications, length of stay, and mortality after major abdominal surgery for gastrointestinal, hepatobiliary and pancreatic malignancies and to identify the risk factors for impaired outcome. MATERIAL AND METHODS: Data of patients, operated on for gastro-intestinal malignancies during 2009-2010 were retrieved from the clinical database of Tartu University Hospital. Major outcome data included incidence of postoperative complications, hospital-, 30-day, 90-day and 1-year mortality, and length of ICU and hospital stay. High-risk patients were defined as patients with American Society of Anesthesiologists (ASA) physical status ≥3 and revised cardiac risk index (RCRI) ≥3. Multivariate analysis was used to determine the risk factors for postoperative mortality and morbidity. RESULTS: A total of 507 (259 men and 248 women, mean age 68.3±11.3 years) were operated on for gastrointestinal, hepatobiliary, or pancreatic malignancies during 2009 and 2010 in Tartu University Hospital, Department of Surgical Oncology. 25% of the patients were classified as high risk patients. The lengths of intensive care and hospital stay were 4.4±7 and 14.5±10 days, respectively. The rate of postoperative complications was 33.5% in the total cohort, and 44% in high-risk patients. The most common complication was delirium, which occurred in 12.8% of patients. For patients without high risk (ASA130min, and positive fluid balance >1300mL after the 1st postoperative day, were identified as independent risk factors for the development of complications. CONCLUSION: The complication rate after major gastro-intestinal surgery is high. ASA physical status and revised cardiac risk index adequately reflect increased risk for postoperative complications and worse short and long-term outcome.

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 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.

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.

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.

Two cases of takotsubo syndrome related to tracheal intubation/extubation.

Takotsubo cardiomyopathy is an acute, reversible left ventricular dysfunction with characteristic contractility disorder and is usually preceded by emotional or physical stress. Two cases of Takotsubo cardiomyopathy related to tracheal manipulation are presented. Both the patients had all the typical symptoms and signs of Takotsubo cardiomyopathy, and both of them recovered completely within weeks. Tracheal manipulation is a well-known stress factor during the perioperative period, and experience from these two cases stresses the crucial role of measures aimed to stress reduction. Proper premedication and calm environment are recommended to produce anxiolysis before intubation. The administration of α- and ß-blockers is also recommended to inhibit sympathetic stress caused by tracheal manipulation.

Distribution of metronidazole in muscle tissue of patients with septic shock and its efficacy against Bacteroides fragilis in vitro.

OBJECTIVES: Studies investigating the target site concentration of antibiotics, such as beta-lactams and fluoroquinolones, have demonstrated differences between the drug concentrations in healthy volunteers and septic patients. The aims of this study were (i) to evaluate the muscle tissue concentration of metronidazole in patients with septic shock and (ii) to test the efficacy of metronidazole in an in vitro pharmacodynamic model at different single doses. MATERIALS AND METHODS: Six patients admitted to the ICU of Tartu University Clinics with a diagnosis of septic shock were studied. Patients receiving metronidazole treatment within 48 h before the study or with a BMI > 35 were excluded. Metronidazole muscle tissue concentration was assessed by a microdialysis technique. Based on the microdialysis data, similar kinetics were simulated in in vitro experiments using Bacillus fragilis strains with MIC(90)s of 0.125 mg/L (BF125) and 1.0 mg/L (BF1). RESULTS: Metronidazole concentrations in plasma achieved a mean (s.d.) value of 11.4+/-2.0 mg/L at 30 min after administration of a single 500 mg intravenous dose, while in the muscle tissue, maximum concentrations of 8.2+/-4.5 mg/L were achieved at 140+/-92.3 min after the dose. When this metronidazole time course was simulated in vitro, the time to 99.9% kill ranged from 1.0 to 1.4 h for BF125 and from 1.8 to 3.5 h for BF1, while the eradication time ranged from 1.7 to 2.5 h and from 3.4 to 6.5 h, respectively. No regrowth was detected. CONCLUSION: Pharmacokinetic-pharmacodynamic simulation of metronidazole interstitial concentrations shows a high efficacy of the drug in septic patients.

Perioperative penetration of metronidazole into muscle tissue: a microdialysis study.

OBJECTIVE: To evaluate the concentration of metronidazole in muscle tissue using microdialysis and to compare it with plasma concentration and in vitro-defined MIC(90) (minimal inhibiting concentration) for the most frequent anaerobic bacteria isolated in our hospital. MATERIALS AND METHODS: Six female patients scheduled for elective gynaecological surgery were included. Exclusion criteria were active inflammatory process and being overweight (BMI more than 30). Microdialysis catheters (CMA 60 catheters with 20 kDa cut-off membrane) were placed into the m. vastus lateralis. The microdialysis perfusion rate was 2 microl/min. To assess in vivo recovery of the drug, retrodialysis with a 5-mg/l solution of metronidazole was performed. Microdialysis and blood samples were collected simultaneously 10 h after metronidazole administration. MIC(90) data were obtained from the database of the microbiology laboratory of the local hospital. RESULTS: Data from five patients were included in analysis. The metronidazole concentration in blood achieved a value of 16.5+/-4.6 mg/l at 30 min (first available data), while in muscle a maximum level of 7.8+/-1.5 mg/l was achieved at 114 min. The mean MIC(90) for the Bacteroides fragilis group was 0.25+/-0.26 mg/l. Data from mean plasma concentrations were fitted into the two-compartmental model and time over MIC(90) and time over four times MIC(90) were calculated, which were 52.1+/-13.5 h and 33.2+/-8.7 h, respectively. The C(max)/MIC(90) ratio was 65.8+/-18.5 for plasma and 31.1+/-6.2 for muscle. CONCLUSION: The present data demonstrate that metronidazole penetrates well into muscle tissue. Muscle tissue concentrations reach values far greater than MIC(90) for the Bacteroides fragilis group and persist at such high levels for at least 10 h.