Assessing the binding interaction of polystyrene sulfonate with amitriptyline in healthy volunteers: a cross-over design - The BIND study.

PURPOSE: Polystyrene sulfonate is used for binding potassium in patients with chronic kidney disease (CKD). Because of its binding properties, it can potentially bind other medications and thereby decrease their bioavailability and effectiveness. Amitriptyline, often used by CKD patients for neuropathic pain, shows significant binding to polystyrene sulfonate in vitro. The purpose of this study was to determine the effect of polystyrene sulfonate on the exposure of amitriptyline in vivo when taken concomitantly in healthy volunteers. METHODS: We performed a prospective cross-over study in nine healthy volunteers. Participants were 18 years of age or older, did not use any medication, and had no known allergy to amitriptyline or polystyrene sulfonate. Participants visited Deventer Teaching Hospital twice. Once they received a single dose of amitriptyline 50 mg and once they received a single dose of both polystyrene sulfonate 15 g and amitriptyline 50 mg taken concomitantly, with a wash out period of at least 1 week. After intake of the medication, six blood samples were collected, at 2, 3, 4, 5, 6, and 8 h. Blood samples were analysed to determine maximum concentration (Cmax) and area under the curve 0-8 h after intake (AUC0-8 h). Difference in Cmax and AUC0-8 h was analysed with a paired T-test or Wilcoxon signed rank test, depending on normality of the data. A p-value < 0.05 was considered statistically significant. RESULTS: Of the nine participants included, eight participants completed both visits to the hospital. Mean maximum concentration (Cmax) of amitriptyline was 35.61 µg l-1 (95% CI 27.90-43.33 µg l-1) when taken alone, compared to 9.25 µg l-1 (95% CI 6.59-11.92 µg l-1) when taken with polystyrene sulfonate (p < 0.001). Mean AUC0-8 h of amitriptyline was 168.20 µg × h l-1 (95% CI 139.95-196.45 µg × h l-1) when taken alone and 45.78 µg × h l-1 (95% CI 30.20-61.36 µg × h l-1) when taken with polystyrene sulfonate (p < 0.0001). CONCLUSION: These results show a significant decrease in exposure of amitriptyline of approximately 75% when taken concomitantly with polystyrene sulfonate, thereby probably compromising therapy efficacy. Patients using both amitriptyline and polystyrene sulfonate should be informed to separate intake of these medications. TRIAL REGISTRATION: NL8539 (17 April 2020).

Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements.

WHAT IS KNOWN AND OBJECTIVE: The reported incidence of metformin associated lactic acidosis (MALA) in type 2 diabetes mellitus (DM) is 3-9 cases per 100,000 patient-years. In clinical practice, 22-94% of patients using metformin have contraindications to metformin, so the incidence of MALA may be higher than reported. AIM OF THE STUDY: To estimate the incidence of MALA in type 2 DM patients by means of metformin serum concentration measurements and investigate the correlation of metformin serum concentration with the clinical outcome of MALA. METHODS: MALA cases were identified by reviewing the medical records of patients with metformin serum concentrations measured between January 2000 and October 2008. MALA was defined as arterial pH <7·35 and lactate concentration >5·0 mmol/L in patients using metformin. The incidence of MALA was calculated from the number of cases and the at risk population. The correlation coefficient between the metformin and lactate concentration was calculated by linear regression. The relationship between metformin serum concentration, lactate concentration and outcome was examined by calculating the mean metformin and lactate concentration in patients who survived and those who died. The Student's t-test was used to compare groups. RESULTS AND DISCUSSION: In 29 patients metformin serum concentration was measured, 16 had MALA. Eleven of the 16 MALA cases (69%) had risk factors for lactic acidosis in their medical history, 13 cases (81%) had renal failure on admission. The incidence of MALA was estimated at 47 per 100,000 patient-years, this is 5-16 times higher than previously reported. This may be explained by the use of metformin in the presence of risk factors for lactic acidosis. Survivors had a higher metformin serum concentration (18·9 mg/L) than non-survivors (2·9 mg/L, P = 0·006) which can be explained by less severe underlying disease in patients who survived MALA, rather than an effect of metformin itself. WHAT IS NEW AND CONCLUSION: The incidence of MALA estimated from metformin serum concentration measurements in type 2 DM patients is 5-16 times higher than reported in literature. MALA is probably caused by the frequent use of metformin in the presence of risk factors for lactic acidosis. Metformin serum concentration measurements may aid in the timely diagnosis and therapy of MALA. The outcome of MALA is determined by the severity of the underlying disease, rather than by metformin itself.

Campylobacter jejuni peritonitis in a patient with liver cirrhosis.

A 56-year-old man with alcoholic liver cirrhosis (Child-Pugh class C), ascites and hepatocellular carcinoma developed acute diarrhoea and fever. Ascites granulocyte count was 5760 per microliters. Campylobacter jejuni grew in cultures from faeces, blood and ascites. The patient was successfully treated with erythromycin. Although the incidence of bacterial infections including peritonitis is high in patients with end-stage liver cirrhosis, this is one of very few cases in which Campylobacter jejuni has been identified as the causative microorganism.

Haemolytic uraemic syndrome following bone marrow transplantation. Case report and review of the literature.

Thrombotic microangiopathy (TMA) can be a late complication of bone marrow transplantation (BMT). A patient is described in whom the haemolytic uraemic syndrome developed 10 months after BMT and who died of E. coli sepsis while on maintenance haemodialysis. The literature is reviewed, regarding clinical presentation, incidence, pathogenesis and therapy. TMA can be observed, after an interval of 3-12 months, in about 6-26% of patients following BMT. Reported cases vary considerably in clinical severity, from mild presentations to severe TMA with high mortality rates despite intensive therapy. Important pathogenetic roles are ascribed to the conditioning total body irradiation and the use of cyclosporin A, but other factors may be involved as well. Next to supportive therapy, plasma exchange and the use of ACE inhibitors may be of value in treating BMT-associated TMA.

Vasodilating prostaglandin E1 decreases critical oxygen delivery by increasing critical oxygen extraction in anesthetized pigs.

The abnormal dependence of O2 uptake (VO2) on O2 delivery (QO2) during severe sepsis, and the adult respiratory distress syndrome (ARDS) may be caused by impaired vascular reactivity, following release of vasodilating prostaglandins. Infusion of these compounds, however, may improve tissue oxygenation. We studied the effect of vasodilating prostaglandin E1 (PGE1; 0.2 microgram/kg/min) on the critical O2 extraction ratio (ERO2c) and the critical QO2 (QO2c) in a saline-controlled, crossover study in 12 barbiturate-anesthetized pigs. QO2, VO2 (independently from QO2), and blood lactate concentrations were measured during graded cardiac output reductions by incremental positive end-expiratory pressure (0-20 cm H2O PEEP, raised by 5 cm H2O at 15 min intervals). At 0 cm H2O PEEP, PGE1 decreased arterial blood pressure, mainly due to a fall in systemic vascular resistance. From 0 to 20 cm H2O PEEP, the fall in QO2 was greater in the PGE1 than in the saline series (P < 0.005), since ventricular filling and the rise in heart rate were less in the former. The decrease in VO2 (P < 0.005) did not differ between series. As estimated from bilinear regression on paired VO2/QO2 data in individual pigs, the QO2c was 9.8 +/- 3.6 (mean +/- SD) during PGE1 and 14.6 +/- 3.8 ml/kg/min during saline infusion (P = 0.008), with ERO2c 68% +/- 16% and 48% +/- 12%, respectively (P < 0.005). The QO2c, estimated from bilinear regression on paired lactate/QO2 data during the first treatment period, was 7.1 +/- 1.2 for PGE1 and 12.8 +/- 4.5 ml/kg/min for saline (P < 0.05), at similar lactate concentrations (2.0 +/- 0.5 and 1.7 +/- 0.5 mmol/liter, respectively). PGE1-induced vasodilation thus decreases QO2c, because of increased ERO2c, probably resulting from capillary recruitment, an increased surface area available for O2 exchange, and decreased O2 diffusion distances. Hence, a reduced ERO2 and abnormal supply dependence of VO2 during severe sepsis and ARDS are not caused by release of vasodilating prostaglandins. In contrast, our results partly explain improved tissue oxygenation with these compounds during abnormal VO2 supply dependence, following sepsis and ARDS.

Arterial and mixed venous blood acid-base balance during hypoperfusion with incremental positive end-expiratory pressure in the pig.

The authors sought to determine how hypoperfusion influences acid-base balance in arterial and mixed venous blood. In anesthetized, ventilated pigs (n = 12), we determined hemodynamics, O2 uptake, CO2 output, dead-space ventilation, arterial and mixed venous blood acid-base balances, and lactate concentrations during graded reductions in cardiac output by incremental positive end-expiratory pressure (PEEP, 0-20 cm H2O). Cardiac output decreased from 3.2 +/- 0.2 (mean +/- SEM) to 1.2 +/- 0.1 L/min at 20 cm H2O PEEP. Oxygen delivery declined more than O2 uptake did by 60% +/- 2% and 27% +/- 2%, respectively. The decrease in CO2 output (by 21% +/- 2%) was less than that in O2 uptake. Fractional dead-space ventilation increased. At a slight increase in carbon dioxide tension (PCO2) of 4 +/- 1 mm Hg, pH decreased in arterial blood from 7.54 +/- 0.01 to 7.47 +/- 0.02 mmol/L, and standard bicarbonate decreased from 30.3 +/- 0.5 to 27.5 +/- 0.6 mmol/L. The decrease in standard bicarbonate exceeded the increase in blood lactate concentrations. At a similar decrease in standard bicarbonate, the decrease in pH was larger (P less than 0.005) in mixed venous blood than in arterial blood owing to a larger increase in PCO2 (from 40 +/- 2 to 50 +/- 2 mm Hg, P less than 0.005). The changes were reversed after discontinuing PEEP. The authors conclude that ischemia after incremental PEEP results in tissue metabolic acidosis with superimposed respiratory acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of energy expenditure by indirect calorimetry in healthy subjects and patients with liver cirrhosis.

The reliability of resting energy expenditure (REE) measurements by indirect calorimetry with a ventilated hood was investigated in 50 healthy controls and 10 patients with liver cirrhosis. In each subject basal energy expenditure (BEE) was determined once and REE three times (morning REE1, noon REE2, afternoon REE3). In controls and patients the first 5-minute BEE and first 5-minute REE (controls also second 5-minute REE) were higher than in the remainder of the 30-minute recording. Only the last 20 minutes of recordings were used to calculate BEE (1645 +/- 315, mean +/- SD, in kilocalories per day), REE1 (1880 +/- 365), REE2 (1782 +/- 384), and REE3 (1775 +/- 316) in controls, and in cirrhotics: BEE (1530 +/- 235), REE1 (1714 +/- 267), REE2 (1715 +/- 238), and REE3 (1779 +/- 275). REE was higher than BEE in controls and cirrhotics (p less than 0.05). The REE variation coefficient was 5 +/- 3% in controls and 5 +/- 2% in cirrhotics. No systematic difference between REE1, REE2, and REE3 was found. Energy expenditure predicted by the Harris-Benedict equation differed up to 21% from measured BEE in individual controls; group mean BEE, however, was correctly predicted. In cirrhotics differences between measured and predicted BEE up to 26% occurred, while measured BEE was higher than predicted BEE (p = 0.06). It is concluded that REE can be reliably assessed by indirect calorimetry with a ventilated hood system in controls and patients at any time of the day, when values obtained in the first 10 minutes are deleted.(ABSTRACT TRUNCATED AT 250 WORDS)

Independent oxygen uptake and oxygen delivery in septic and postoperative patients.

Previous studies reporting pathologic oxygen supply dependency calculated VO2 as CO x C(a-v)O2. We investigated whether pathologic oxygen supply dependency exists in septic and postoperative patients if VO2 and DO2 are assessed independently. In septic patients, VO2 was 164 +/- 31 and DO2 was 633 +/- 209 ml/min/m2. The slope (b) of the VO2-DO2 regression line VO2 = b x DO2 + a ranged from -0.10 to 0.08 (mean, 0.02 +/- 0.01, p less than 0.05) and was statistically significant in two patients (b = 0.05 and b = 0.08, p less than 0.05). In postoperative patients VO2 was 136 +/- 19 and DO2 was 481 +/- 160 ml/min/m2; b ranged from -0.07 to 0.09 (mean, 0.04 +/- 0.01, p less than 0.001) and was statistically significant in one patient (b = 0.09, p less than 0.01). The lack of a close relationship between independently measured VO2 and DO2 may indicate that septic and postoperative patients in stable hemodynamic condition have no pathologic oxygen supply dependency. Analysis of the VO2-DO2 relationship may not be useful to guide therapy or predict outcome.

Oxygen delivery and oxygen uptake in postoperative and septic patients.

Pathologic dependency of VO2 on DO2 has been reported in postoperative and septic patients. We studied the influence of an artifact due to calculation of VO2 from CO and AV content difference. In 13 postoperative and seven septic patients, the relationships between DO2 and cVO2 and between DO2 and mVO2 were analyzed by linear regression. In ten patients, cVO2 and DO2 were significantly correlated, but in only two of these patients mVO2 also correlated with DO2. In two patients, there was a significant correlation between mVO2 and DO2. The main contribution to the correlation and to the slope of the regression line between cVO2 and DO2 may be due to mathematic coupling of cVO2 and DO2. With cVO2, erroneous conclusions concerning the VO2-DO2 relationship may be drawn. In four patients, DO2 and mVO2 were significantly related, reflecting either physiologic coupling or pathologic supply dependency of VO2.

Day-to-day variability of energy expenditure in critically ill surgical patients.

To determine whether the total energy expenditure (TEE) determined on a single day reliably estimates TEE on subsequent days of a patient's ICU stay, day-to-day variability of TEE and its relation to clinical condition were assessed. TEE was measured by indirect calorimetry in 60 mechanically ventilated critically ill surgical patients during a 2 to 7-day period. Clinical condition was scored by daily determination of the simplified acute physiology score (SAPS). Day-to-day variation of TEE was significantly (p less than .0001) influenced by body temperature, but not by SAPS or day of measurement. In the individual patient, day-to-day variability of TEE may be large. When TEE on day 1 is used to estimate TEE on subsequent days, errors of up to 31% of actual TEE occurred. Addition of a temperature correction reduced the maximum error to 25%. If a balance between caloric supply and demand is intended, it is advised to adapt the caloric supply to the result of daily TEE measurement by indirect calorimetry.

Accuracy of intermittent metabolic gas exchange recordings extrapolated for diurnal variation.

In the treatment of critically ill patients, it may be important to know the values of total diurnal O2 consumption and CO2 production. Often, diurnal values are obtained by extrapolation from the easily obtained short interval values. However, both stochastic and systematic errors can be introduced. This study analyzes the systematic influence of a possible diurnal variation of gas exchange and quantifies the extrapolation accuracy of 16 commonly used recording protocols (one to four times a day for 5, 15, 30, and 60 min). Continuous gas exchange measurements were performed for 24 h in 50 ventilated patients and compared to extrapolated results. Only a small diurnal variation was found, and extrapolation accuracy depended on the duration and, especially, the number of recording periods. In clinical practice, 24-h values can be estimated with sufficient accuracy by extrapolation from two 15-min measurements per day.

Outcome prediction in critically ill patients by means of oxygen consumption index and simplified acute physiology score.

Both oxygen consumption index (VO2-index) and simplified acute physiology score (SAPS) are reported to be reliable predictors of the ultimate outcome in critically ill patients. The purpose of this study was to verify whether survivors and nonsurvivors have different VO2-indices and whether the prognostic potency of SAPS can be improved by addition of VO2-index as a supplemental physiological variable. In 50 mechanically ventilated surgical ICU patients with heterogeneous underlying diseases, SAPS was calculated and VO2-index was determined by continuous 24-h measurement of oxygen consumption. The VO2-indices of survivors and nonsurvivors were not significantly different (p greater than 0.05), which is in contrast to the results of earlier studies. This contrast may be explained by a difference both in methods of VO2-measurement and in study populations. SAPS was significantly lower in survivors than in nonsurvivors (p less than 0.005) and was able to classify the patients correctly into groups of increasing probability of death. However, SAPS failed to be a helpful prognosticator in the individual patient. The addition of VO2-index to SAPS as a supplemental physiological variable did not substantially improve the prognostic potency. Because a higher VO2-index did not necessarily indicate a better survival chance, there is no argument for therapeutic interventions aimed exclusively at increasing VO2-index, as suggested previously.

Total parenteral nutrition in critically ill surgical patients: fixed vs tailored caloric replacement.

In critically ill patients accurate measurement of total energy expenditure (TEE) is possible by means of continuous indirect calorimetry. Since in many ICUs the necessary equipment is not available, the Harris-Benedict formula (HB) is frequently used to calculate TEE. Supplemental application of a clinical correction factor (HBc) has been advised. In this study we assessed the reliability of both methods of calculation and of a standard nutritional regimen, all three compared to the calorimetrically measured TEE (gold standard). Although the basic HB-formula did not perform better than the standard regimen, significantly better results were obtained by supplemental application of the clinical correction factor (HBc). It is left undecided, whether or not indirect calorimetry is actually to be preferred in daily clinical practice.

Calculation versus measurement of total energy expenditure.

In acutely ill patients both hypo- and hyperalimentation must be avoided by adjusting caloric intake to total energy expenditure (TEE). We determined the discrepancy between basal energy expenditure (BEE) calculated from the basic Harris-Benedict formula and TEE measured by continuous indirect calorimetry in a heterogeneous group of mechanically ventilated surgical patients. We also compared the accuracy of TEE calculated from the corrected Harris-Benedict formula or estimated by intermittent indirect calorimetry to that of TEE measured by continuous indirect calorimetry. The poor correlation between calculated BEE and measured TEE was significantly (p less than .05) improved by a correction factor based on each patient's clinical condition. The mean absolute difference between calculated TEE and measured TEE was 8.9 +/- 9.6 (SD) %. Calculations were significantly (p less than .05) improved by estimating TEE from two 5-min recording periods, which suggests that continuous indirect calorimetry may not always be necessary to guide caloric replacement.

Artifacts in the assessment of metabolic gas exchange.

In mechanically ventilated patients metabolic gas exchange recordings are frequently influenced by routine patient therapy. In this study the influence of such artifacts is investigated and a method for automatic detection and suppression proposed. This method reduced the influence of artifacts on diurnal oxygen and carbon dioxide exchange from up to 10% to a maximum of 1%.