Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of s... more Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of six patients with severe peritonitis and septic shock and to relate measured concentrations to the minimum inhibitory concentration of bacteria. Microdialysis catheters were placed into the peritoneal space during surgery. Meropenem concentrations in plasma and in PF were analyzed using compartmental modeling. Meropenem areas under the concentration-time curve were lower in PF than in plasma (average ratio, 73.8+/-15%) because of degradation confirmed ex vivo. Compartment modeling with elimination from a peripheral compartment described the data adequately, and was used to simulate steady-state concentration profiles in plasma and PF during various dosing regimens. At the currently recommended dosing regimen of 1 g infused over 20 min every 8 h, PF concentrations of meropenem in patients with severe peritonitis associated with septic shock reach values sufficient for antibacterial effects...
Microvascular alterations and intra-abdominal hypertension are both involved in development of or... more 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. Transient increase in IAP induced by pneumoperitoneum affects sublingual microcirculation. 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. 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 w...
Takotsubo cardiomyopathy is an acute, reversible left ventricular dysfunction with characteristic... more 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 β-blockers is also recommended to inhibit sympathetic stress caused by tracheal manipulation.
Purpose. We hypothesize that intra-abdominal hypertension (IAH) is associated with the presence o... more 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 intraabdominal 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.
Background: The development of intra-abdominal hypertension [IAH] in critically ill patients admi... more 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.
Objective: To evaluate the concentration of metronidazole in muscle tissue using microdialysis an... more Objective: To evaluate the concentration of metronidazole in muscle tissue using microdialysis and to compare it with plasma concentration and in vitrodefined 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 ll/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.
A rapid and sensitive LC-UV method was developed and validated for the determination of meropenem... more A rapid and sensitive LC-UV method was developed and validated for the determination of meropenem, in human plasma and urine. Meropenem retention time was 4.8 min. Method development was based on comparative analysis of different extraction methods published as well as careful study of meropenem stability in biological samples under different conditions. Best results in plasma sample preparation were obtained from protein precipitation with methanol. LOQ was 0.1 lg mL -1 for plasma and 1 lg mL -1 for urine samples. Meropenem in plasma has low stability at room temperature (<20% of original content after 12 h), but had acceptable stability when the whole analysis procedure was designed to minimize the exposure of meropenem-containing samples and solutions to temperatures higher than 4°C. The developed method was applied to a human pharmacokinetic study in patients with acute peritonitis.
a b s t r a c t a r t i c l e i n f o Keywords: Sublingual microcirculation Intra-abdominal press... more a b s t r a c t a r t i c l e i n f o Keywords: Sublingual microcirculation Intra-abdominal pressure Intra-abdominal hypertension Sidestream dark field imaging Critically ill patients
Objectives: Studies investigating the target site concentration of antibiotics, such as b-lactams... more Objectives: Studies investigating the target site concentration of antibiotics, such as b-lactams and fluoroquinolones, have demonstrated differences between the drug concentrations in healthy volun- teers 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
Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of s... more Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of six patients with severe peritonitis and septic shock and to relate measured concentrations to the minimum inhibitory concentration of bacteria. Microdialysis catheters were placed into the peritoneal space during surgery. Meropenem concentrations in plasma and in PF were analyzed using compartmental modeling. Meropenem areas under the concentration-time curve were lower in PF than in plasma (average ratio, 73.8+/-15%) because of degradation confirmed ex vivo. Compartment modeling with elimination from a peripheral compartment described the data adequately, and was used to simulate steady-state concentration profiles in plasma and PF during various dosing regimens. At the currently recommended dosing regimen of 1 g infused over 20 min every 8 h, PF concentrations of meropenem in patients with severe peritonitis associated with septic shock reach values sufficient for antibacterial effects...
Microvascular alterations and intra-abdominal hypertension are both involved in development of or... more 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. Transient increase in IAP induced by pneumoperitoneum affects sublingual microcirculation. 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. 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 w...
Takotsubo cardiomyopathy is an acute, reversible left ventricular dysfunction with characteristic... more 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 β-blockers is also recommended to inhibit sympathetic stress caused by tracheal manipulation.
Purpose. We hypothesize that intra-abdominal hypertension (IAH) is associated with the presence o... more 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 intraabdominal 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.
Background: The development of intra-abdominal hypertension [IAH] in critically ill patients admi... more 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.
Objective: To evaluate the concentration of metronidazole in muscle tissue using microdialysis an... more Objective: To evaluate the concentration of metronidazole in muscle tissue using microdialysis and to compare it with plasma concentration and in vitrodefined 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 ll/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.
A rapid and sensitive LC-UV method was developed and validated for the determination of meropenem... more A rapid and sensitive LC-UV method was developed and validated for the determination of meropenem, in human plasma and urine. Meropenem retention time was 4.8 min. Method development was based on comparative analysis of different extraction methods published as well as careful study of meropenem stability in biological samples under different conditions. Best results in plasma sample preparation were obtained from protein precipitation with methanol. LOQ was 0.1 lg mL -1 for plasma and 1 lg mL -1 for urine samples. Meropenem in plasma has low stability at room temperature (<20% of original content after 12 h), but had acceptable stability when the whole analysis procedure was designed to minimize the exposure of meropenem-containing samples and solutions to temperatures higher than 4°C. The developed method was applied to a human pharmacokinetic study in patients with acute peritonitis.
a b s t r a c t a r t i c l e i n f o Keywords: Sublingual microcirculation Intra-abdominal press... more a b s t r a c t a r t i c l e i n f o Keywords: Sublingual microcirculation Intra-abdominal pressure Intra-abdominal hypertension Sidestream dark field imaging Critically ill patients
Objectives: Studies investigating the target site concentration of antibiotics, such as b-lactams... more Objectives: Studies investigating the target site concentration of antibiotics, such as b-lactams and fluoroquinolones, have demonstrated differences between the drug concentrations in healthy volun- teers 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
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