Clinical pharmacology of exogenously administered alkaline phosphatase.

PURPOSE: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). METHODS: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg(-1) 24 h(-1)) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. RESULTS: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. CONCLUSIONS: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis.

Acetic acid as a decontamination method for ICU sink drains colonized by carbapenemase-producing Enterobacteriaceae and its effect on CPE infections.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) are emerging pathogens representing a major concern for public health. In Belgium, the OXA-48 carbapenemase resistance gene is identified most frequently. Sink drains in intensive care units (ICUs) are known to be colonized by Gram-negative bacilli. A correlation between environmental contamination and CPE infections in ICUs has been established. A long-term CPE epidemic in a local ICU proved difficult to control. METHODS AND RESULTS: A variety of CPE strains, all carrying the OXA-48 resistance gene, were isolated from almost all sinks in patient rooms in the ICU. Decontamination of the sinks with 250 mL 25% acetic acid three times weekly was implemented. Sink drain colonization was followed up for six months thereafter. Both the number of CPE-colonized sinks and the number of patients colonized or infected with CPE decreased drastically, to the extent that the epidemic was considered to be eradicated. In-vitro growth of all isolates was inhibited by a concentration of acetic acid equal to or smaller than that used for decontamination. Epidemiological analysis demonstrated a positive and significant relationship between contaminated sinks and CPE acquisition of patients admitted to ICU rooms, indicating the importance of contaminated sinks as the environmental reservoir of the epidemic. CONCLUSION: Decontamination of sink drains with acetic acid is a valuable alternative to other methods, such as heated sinks and water-free care, especially when other options are not feasible in the short term. Acetic acid is cheap, widely available, effective and manageable from a safety and technical point of view.

Regional arteriovenous differences in P(CO2) and pH can reflect critical organ oxygen delivery during endotoxemia.

The goal of this study was to assess whether serial measurements of regional veno-arterial PcoC2 (VAPco2) and arteriovenous pH (AVpH) differences reflect the onset of tissue hypoxia in various organs during endotoxemia. In 12 anesthetized, mechanically ventilated dogs, ultrasonic flow probes were placed around superior mesenteric, renal, and femoral arteries to measure regional blood flow. The corresponding veins were cannulated for blood sampling. Oxygen uptake (V02) was determined from exhaled gas analysis, and oxygen delivery (D02) was calculated as the product of thermodilution cardiac output and arterial oxygen content. Six dogs served as controls, and six received Escherichia coli endotoxin. Cardiac tamponade was induced to reduce D02. Systemic, mesenteric, and femoral critical D02 (DO2crit) were higher in the endotoxic than in the control group (systemic: 12.1 + or - 2.2 vs. 7.9 + or - 2.6 mL/kg min; mesenteric: 8.2 + or - 2.5 vs. 4.1 + or - .6 mL/100 g tissue-min; femoral: 8.3 + or - 2.3 vs. 4.6 + or - .9 mL/min; all p < .05). Systemic and regional critical oxygen extraction ratio (O2ERcrit) were lower in the endotoxic than in the control group (systemic: 45.1 + or - 9.7 vs. 74.1 + or - 9.1%; mesenteric: 37.1 + or - 15.4 vs. 71.1 + or - 7.4%; renal: 30.7 + or - 24.6 vs. 53.9 + or - 28.7%; femoral: 48.1 + or - 9.2 vs. 75.3 + or - 6.9%; all p < .05). With and without endotoxin, systemic and regional DO2crit calculated from V02, VAPco2, or AVpH were similar. In conclusion, systemic and regional VAPco2 and AVpH gradients can reflect hypoxic threshold in the presence, as in the absence, of endotoxemia.

Treatment with a platelet-activating factor antagonist has little protective effects during endotoxic shock in the dog.

Platelet-activating factor (PAF) is a potent vasoactive and inflammatory lipid mediator which has been implicated in the hemodynamic alterations of endotoxemia and sepsis. Different PAF receptor antagonists have been shown to attenuate the systemic and pulmonary disturbances of sepsis, but they were generally administered before the injection of endotoxin and their effects have not been consistent. To examine the effects of BB-882, a novel potent PAF receptor antagonist, on general hemodynamics and regional flow distribution in a canine endotoxic shock model, 14 anesthetized and ventilated dogs received 2 mg/kg of Escherichia coli endotoxin intravenously (i.v.) followed by generous fluid resuscitation. Thirty minutes later, the dogs received either BB-882 (n = 7) as a continuous i.v. infusion with hourly increasing doses (2, 5, and 10 mg/kg.h, respectively) or a corresponding amount of saline (n = 7). The administration of BB-882 resulted in a dose-dependent reduction in cardiac output and an increase in systemic and pulmonary vascular resistance. Mesenteric and renal flow were not different from control values whereas femoral blood flow progressively decreased. Another group of 7 dogs received 5 mg/kg i.v. bolus of BB-882 30 min before endotoxin. Pretreatment significantly increased mesenteric blood flow by about 50% but did not show any significant hemodynamic effects. This study demonstrates that the administration of a PAF receptor antagonist following endotoxic shock in fluid resuscitated dogs does not offer significant hemodynamic benefit. Pretreatment with BB-882 at the dose used only enhanced mesenteric perfusion. These findings do not support beneficial effects of PAF receptor antagonists in septic shock.

Erythropoietin response is blunted in critically ill patients.

OBJECTIVES: Critically ill patients often develop anaemia which can be related to a number of factors. However, the exact causes of anaemia in many patients remain unexplained. We hypothesized that the relationship between erythropoietin (EPO) and haematocrit may be altered in critically ill patients. DESIGN: Serum concentrations of EPO were serially determined by the ELISA method in 36 critically ill, non-hypoxaemic patients who stayed more than 7 days in the Intensive Care Unit, including 22 patients with sepsis and 14 without. Eighteen ambulatory patients with iron-deficiency anaemia served as a control group. SETTING: Two University Hospital Intensive Care Departments. RESULTS: A significant inverse correlation between serum EPO and haematocrit levels was found in the control patients (r = -0.81, p < 0.001), but not in the critically ill patients (r = -0.09, NS), except in a subgroup of non-septic patients without renal failure (r = -0.61, p < 0.01). CONCLUSIONS: EPO levels can be inappropriately low in critically ill patients, so that EPO deficiency may contribute to the development of anaemia in these patients. This phenomenon is observed not only in the presence of acute renal failure, but also in the presence of sepsis.

Effects of nitric oxide on blood flow distribution and O2 extraction capabilities during endotoxic shock.

The effects of the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) and the NO donor 3-morpholinosydnonimine (SIN-1) were tested in 18 endotoxic dogs. L-NMMA infusion (10 mg . kg-1 . h-1) increased arterial and pulmonary artery pressures and systemic and pulmonary vascular resistances but decreased cardiac index, left ventricular stroke work index, and blood flow to the hepatic, portal, mesenteric, and renal beds. SIN-1 infusion (2 microg . kg-1 . min-1) increased cardiac index; left ventricular stroke work index; and hepatic, portal, and mesenteric blood flow. It did not significantly influence arterial and pulmonary artery pressures but decreased renal blood flow. The critical O2 delivery was similar in the L-NMMA group and in the control group (13.3 +/- 1.6 vs. 12.8 +/- 3.3 ml . kg-1 . min-1) but lower in the SIN-1 group (9.1 +/- 1.8 ml . kg-1 . min-1, both P < 0.05). The critical O2 extraction ratio was also higher in the SIN-1 group than in the other groups (58.7 +/- 10.6 vs. 42.2 +/- 7.6% in controls, P < 0.05; 43.0 +/- 15.5% in L-NMMA group, P = not significant). We conclude that NO is not implicated in the alterations in O2 extraction capabilities observed early after endotoxin administration.

Hemofiltration treatment for sepsis: is it time for controlled trials?

While the use of hemofiltration to treat septic shock has potential benefits, the existing studies are difficult to compare because of their variety of inclusion criteria. The concept is to remove the various mediators of severe sepsis and septic shock, such as cytokines and eicosanoids, so that acute renal failure and the resultant multi-organ failure and possible death can be delayed or prevented. The dilemmas include: (a) hemofiltration cannot distinguish between these pro-inflammatory mediators as they are of similar molecular weights, and thus it is difficult to determine which one or combination should be eliminated for the best hemodynamics; (b) timing of the hemofiltration to remove a particular cytokine may make a difference in patient outcome; (c) the most efficacious convection rate of ultrafiltration has not been determined yet; (d) since these mediators quickly saturate the membrane, it should be frequently changed, and thus biocompatibility, availability and costs are added issues; (e) the choice of buffer is different according to the diagnosis of these critically ill patients. Before designing clinical trials, further experimentation is necessary to explore these problems.

Effects of nitric oxide donor SIN-1 on oxygen availability and regional blood flow during endotoxic shock.

BACKGROUND: An excessive release of nitric oxide (NO) has been incriminated in the circulatory disturbances of septic shock. OBJECTIVE: To study the effects of an NO donor, 3-morpholinosydnonimine (SIN-1), an oxygen availability and regional blood flow during endotoxic shock to see if a beneficial effect of NO synthase inhibitors in septic shock could be conclusively demonstrated. MATERIALS AND METHODS: In 14 anesthetized and mechanically ventilated dogs, global invasive hemodynamic monitoring was completed and ultrasonic flow probes were placed around the superior mesenteric, left renal, and left femoral arteries for simultaneous measurements of regional blood flow. All dogs received Escherichia coli endotoxin, 2 mg/kg. A control group (n = 7) was administered saline at 20 mL/kg per hour, and a SIN-1 group (n = 7) was given a combination of saline with SIN-1 at successive doses of 1, 2, and 4 micrograms/kg per minute. RESULTS: Neither systemic nor pulmonary arterial pressures were influenced by SIN-1. Cardiac index, stroke index, and left ventricular stroke work index did increase at low to moderate doses of SIN-1 but tended to decrease at the highest dose. Systemic and pulmonary vascular resistances decreased. Fractional blood flow increased in the mesenteric bed at all doses used, was not influenced in the renal bed, but decreased in the femoral bed at the highest dose. Oxygen-derived variables were similar in the 2 groups. Blood lactate and plasma concentrations of tumor necrosis factor were not significantly influenced. At the end of the SIN-1 infusion, the administration of 5 mg/kg of methylene blue increased arterial pressure, pulmonary arterial pressure, and systemic and pulmonary vascular resistances but decreased cardiac index and regional blood flow. CONCLUSIONS: The administration of low to moderate doses of the NO donor SIN-1 can significantly increase cardiac index and superior mesenteric blood flow without deleterious effects on arterial pressure in this model of endotoxic shock. These findings support the hypothesis that NO is essential to maintain organ blood flow even during endotoxic shock.

Importance of volume factors in dialysis related hypertension.

OBJECTIVE: To evaluate the relation between total body water and dialysis related hypertension. PATIENTS AND METHODS: Thirty stable chronic hemodialysis patients were studied. Twenty-four-hour ambulatory blood pressure on the day before dialysis, blood pressure before and after dialysis, weight gain, ultrafiltration and total body water were determined. Total body water was measured by body impedance analysis and expressed as percentage of dry weight (TBW %). Ambulatory blood pressure recordings were defined as hypertensive when the blood pressure load (% of readings above 140/90 mmHg) was more than 40%. RESULTS AND CONCLUSION: Patients, classified as normotensive (n = 11) or hypertensive (n = 19), based on 24-hour blood pressure measurements, had significantly different TBW % (54.7 +/- 5.3 vs. 58.9 +/- 4.6%, p = 0.046). Ambulatory blood pressure and postdialysis blood pressure, but not predialysis blood pressure, were significantly correlated with TBW %. Acute volume changes, as reflected by interdialytic weight gain and ultrafiltration did not correlate with TBW %. These changes correlated weakly with predialysis blood pressure. Multivariate analysis showed that only TBW % and antihypertensive medication had an independent influence on 24-hour blood pressure measurements. We conclude that 24-hour blood pressure and blood pressure after dialysis are better related to total body water than blood pressure before dialysis, which was however weakly related to the acute volume overload, induced by interdialytic weight gain. We hypothesize that this could be the result of a more important chronic volume overload leading to an increase in systemic vascular resistance. On the contrary the acute but less important changes in extracellular volume between dialyses cause no hypertension after dialysis and no sustained hypertension over 24 hours, but only in some cases a temporary increase in the blood pressure just before dialysis. This volume overload can be easily determined by measurement of total body water by bioelectrical impedance analysis.

Vanishing pulmonary hypertension in mixed connective tissue disease.

A 29-year-old woman with mixed connective tissue disease presented with signs of progressive pulmonary hypertension. After admission to the hospital her condition worsened rapidly and she developed a cardiac arrest resistant to cardiopulmonary resuscitation. Therefore, emergency extracorporeal assist was performed. No pulmonary embolism was found. Right heart catheterisation showed severe pulmonary hypertension, which was treated with nitric oxide ventilation. She was weaned from the extracorporeal assist with high doses of inotropic agents. Because of suspicion of exacerbation of her underlying disease, which led to pulmonary hypertension, immunosuppressive treatment was started with high doses of corticosteroids and plasma exchange. This resulted in slow recovery over the next four weeks. Control echocardiography showed complete normalisation of cardiac function without signs of pulmonary hypertension. Two months after admission she was discharged from the hospital in good condition.

Escherichia coli endocarditis of a native mitral valve with paravalvular pseudoaneurysm formation and fatal hemopericardium.

Until recently only few cases have been described of acute infective endocarditis with E. Coli limited to a normal native mitral valve. Furthermore, mechanisms of so called abcess formation and rupture are still uncompletely understood. We report the case of an E. Coli endocarditis developing a rapidly progressive pseudoaneurysm of the mitral annulus. At necropsy diffuse infectious tissue weakening with pseudoaneurysm formation of the mitral ring and dissection into an hemorraghic pericard were seen. The authors further discuss the changing pattern of infectious agents causing acute infective endocarditis of the native mitral valve, transesophageal echocardiographic characteristics of paravalvular cavities and insights in mechanisms of pseudoaneurysm formation and dissection from clinicopathological findings.

Use of an Amplatzer Device for Endoscopic Closure of a Large Bronchopleural Fistula following Lobectomy for a Stage I Squamous Cell Carcinoma.

Bronchopleural fistulas can occur as a rare but severe complication after pulmonary resection. Established guidelines for the proper treatment of patients with bronchopleural fistulas do not exist. Apart from attempts to close the fistula, emphasis is placed on preventive measures, early treatment with antibiotics, drainage of the empyema and aggressive nutritional and rehabilitative support. For inoperable patients, endoscopic procedures are the only therapeutic option. Unfortunately, large (>8 mm) or central bronchopleural fistulas are usually not suitable for such endoscopic management. Recently, some groups have published a few case reports about a novel technique for the endobronchial closure of bronchopleural fistulas, using an Amplatzer device, originally designed for transcatheter closure of cardiac septal defects. We applied the same technique as a life-saving treatment in a ventilated patient who was considered inoperable due to a high oxygen need. The operation was successful. The patient could be weaned from ventilation and was eventually discharged from the hospital to a rehabilitation facility several weeks after the insertion of the device. Until now, endoscopic techniques have only been useful for the treatment of small, peripheral, bronchopleural fistulas and even then only as a bridge to surgery in high-risk surgical patients. In this case report, we demonstrate that the use of an Amplatzer device can expand the importance of endoscopic techniques in the treatment of bronchopleural fistulas. An Amplatzer device, for endobronchial closure, can indeed be administered for large and central bronchopleural fistulas. Moreover, it can be considered as a definite alternative to surgery in inoperable patients.

90-day follow-up of patients treated with Drotrecogin Alfa (activated) for severe sepsis: a Belgian open label study.

INTRODUCTION: Severe sepsis is the major cause of mortality in intensive care units (ICUs). The BOOST study (= B (Belgian) OO (Open Label) ST (Study)) is a Belgian open-label trial designed to pragmatically assess the safety and efficacy of Drotrecogin Alfa (activated) (DAA), the only registered treatment in this indication with favourable ratio benefit/risk. METHODOLOGY: Adult patients with severe sepsis and 2 or more sepsis-induced organ dysfunctions (OD) within the 48-hour period preceding the treatment (DAA at 24 microg/kg/h for 96 hours), were included between January 2003 and October 2003. Platelet count < 30 000/mm3 and increased risk for bleeding were exclusion criteria. Mortality and location were evaluated at 28 and 90 days. RESULTS: Of the 100 included patients, 97 (median age: 66 years; men/women: 57/40) were treated and completed the study. The predominant infection sites were lung (49%) and abdomen (29%) and 35% had had recent surgery. The mean and median numbers of OD were 3.4 and 3.0, respectively, and most patients (80 %; 77/97) had 3 or more organ failures at baseline, predominantly respiratory (95%) and cardiovascular (87%). The mean APACHE II score was 25.3 (range: 6-53). The 28-day mortality rate was 32.0% (90% CI: 24.2-39.7) and increased with the number of OD: from 15% (1.9-28.1) for2 ODs, to 71% (52.4-88.8) for 5 ODs. At day 28, the 66 surviving patients were located in general ward (35%), in the ICU (32%) or at home (30%). The 90-day mortality rate was 42% (90% CI: 34.0-50.5), with most of the survivors (73%) staying at home. Eight serious adverse events, including 4 bleedings, were reported between study days 2 and 5, in 5 patients (5.2%) and led to death in 2 patients (2.1%). CONCLUSION: Despite a higher severity of illness at baseline, this phase IV open-label long-term study in Belgian ICUs shows consistent results with previous studies with DAA. Importantly, most of the surviving patients at day 90 were staying at home.

A registry of patients treated with drotrecogin alfa (activated) in Belgian intensive care units--an observational study.

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is the only specific sepsis therapy that has been shown to reduce mortality. The objectives of this study were to document the profile of patients treated with DrotAA in Belgian intensive care units (ICUs), using data from a database established as part of drug reimbursement conditions in Belgium, and to compare the observed hospital mortality of these patients with their expected mortality, calculated using data from non-DrotAA-treated patients from the Belgian section of PROGRESS, a separate, voluntary, international sepsis registry collecting data from patients with severe sepsis. MATERIAL AND METHODS: Data from the non-DrotAA-treated patients in PROGRESS were used to calculate the expected mortality rates for DrotAA-treated patients in the Belgian registry. Using a logistic regression equation, these rates were controlled for age and the presence or absence of organ dysfunction in each of 5 organ systems. The same logistic regression technique was used to control the mortality rates observed in the DrotAA-treated patients from the Belgian registry for age and the presence or absence of each of the 5 organ dysfunctions. Adjusted expected and observed hospital mortality rates could then be compared. RESULTS: There were 436 DrotAA patients in the Belgian registry. Almost all the patients (99.5%) had at least 2 organ failures and the hospital mortality was 51.6%. Two hundred and eighty-six of the patients had enough baseline data to be included in the regression model. Using data from the PROGRESS non-DrotAA patients, the predicted hospital mortality, controlled for age and organ dysfunction, of Belgian registry patients, had they not been treated with DrotAA, was 63.5%. The observed hospital mortality, again controlled for age and organ dysfunction, of the 286 Belgian registry patients was 50.7%, implying an adjusted absolute mortality reduction of 12.8%. CONCLUSIONS: Comparing Belgian reimbursement registry data with those of a voluntary severe sepsis register provides support for the observation that DrotAA reduces mortality rates in severe sepsis and septic shock.

Renal implications of increased intra-abdominal pressure: are the kidneys the canary for abdominal hypertension?

INTRODUCTION: Increased intra-abdominal pressure (IAP) or intra-abdominal hypertension (IAH) is a cause of organ dysfunction in critically ill patients and is independently associated with mortality. The kidneys seem to be especially vulnerable to IAH induced dysfunction and renal failure is one of the most consistently described organ dysfunctions associated with IAH. The aim of this paper is to review the historical background, awareness, definitions, pathophysiologic implications and treatment options for IAP induced renal failure. METHODS: This review will focus on the available literature on IAH-induced renal dysfunction. A Medline and PubMed search was performed in order to find an answer to the question "What is the impact of increased IAP on renal function in the critically ill?". The resulting references were included in the current review on the basis of relevance and scientific merit. RESULTS: Renal dysfunction in IAH is a multifactorial process. The mechanisms involved have not been clarified completely. However, decreased cardiac output, altered renal blood flow and hormonal changes have been implicated. Decompression seems to have a beneficial effect on renal dysfunction, although there are some conflicting data. This may be due to the fact that there is no consensus on indications for decompression, both in terms of IAP values and of timing. An overview of current literature is provided and some interesting leads for future research are suggested. CONCLUSION: IAH can cause renal dysfunction. Therefore, IAP measurements should be considered in our daily practice and preventive measures should be taken to avoid (deterioration of) renal failure in patients with IAH. Decompression may have a beneficial effect in patients with established IAH and renal failure.

Renal implications of increased intra-abdominal pressure: are the kidneys the canary for abdominal hypertension?

INTRODUCTION: Increased intra-abdominal pressure (IAP) or intra-abdominal hypertension (IAH) is a cause of organ dysfunction in critically ill patients and is independently associated with mortality. The kidneys seem to be especially vulnerable to IAH induced dysfunction and renal failure is one of the most consistently described organ dysfunctions associated with IAH. The aim of this paper is to review the historical background, awareness, definitions, pathophysiologic implications and treatment options for IAP induced renal failure. METHODS: This review will focus on the available literature on IAH-induced renal dysfunction. A Medline and PubMed search was performed in order to find an answer to the question "What is the impact of increased IAP on renal function in the critically ill?". The resulting references were included in the current review on the basis of relevance and scientific merit. RESULTS: Renal dysfunction in IAH is a multifactorial process. The mechanisms involved have not been clarified completely. However, decreased cardiac output, altered renal blood flow and hormonal changes have been implicated. Decompression seems to have a beneficial effect on renal dysfunction, although there are some conflicting data. This may be due to the fact that there is no consensus on indications for decompression, both in terms of IAP values and of timing. An overview of current literature is provided and some interesting leads for future research are suggested. CONCLUSION: IAH can cause renal dysfunction. Therefore, IAP measurements should be considered in our daily practice and preventive measures should be taken to avoid (deterioration of) renal failure in patients with IAH. Decompression may have a beneficial effect in patients with established IAH and renal failure.

Occult tuberculous postpneumonectomy space empyema four years after lung resection.

We describe a patient in whom a tuberculous postpneumonectomy empyema developed 4 years after resection for lung cancer. The clinical presentation was dominated by non-specific constitutional symptoms, without any chest complaints. A computed tomographic scan of the chest suggested inflammation in the postpneumonectomy space. Ultimately Mycobacterium tuberculosis was cultured from material aspirated by needle thoracocentesis. To our knowledge this is the first report of a tuberculous postpneumonectomy empyema complicating resection for cancer.

Effect of the infusion of magnesium sulfate during atrial pacing on ECG intervals, serum electrolytes, and blood pressure.

Magnesium salts have been used for decades for the empiric treatment of arrhythmias, particularly torsades de pointes, associated with long QT syndrome. The mechanism underlying this antiarrhythmic effect is still not clear. Therefore the effect of intravenous MgSO4 on serum electrolytes, blood pressure, and ECG variables was evaluated in nine patients with sick sinus syndrome, equipped with a DDD pulse generator, programmed in the atrial asynchronous mode. A total dose of 10 gm MgSO4 was given intravenously over 6 hours at a constant rate. Blood pressure and serum electrolytes were determined before (t0), 3 hours after (t3), and at the end of the magnesium infusion (t6). ECG variables were measured at t0, t3, and t6 at different pacing frequencies (60, 80, and 100 beats/min). Serum magnesium levels rose significantly from 0.88 mmol.l-1 at t0 to 1.91 mmol.l-1 at t6 (p less than 0.05). Magnesium infusion did not affect blood pressure, pulse rate, PR or QRS or QT interval. Increasing the pacing frequency resulted in a statistically significant QT shortening at each serum magnesium level. We conclude that intravenous magnesium administration does not influence the QT interval. Increasing atrial pacing rate shortens the QT interval and this QT shortening is not affected by magnesium. Sustained serum magnesium levels between 1.5 and 2 mmol.l-1 are hemodynamically well tolerated and do not give rise to the development of higher degree atrioventricular block.

Corticosteroids contribute to muscle weakness in chronic airflow obstruction.

Twenty-one patients with chronic obstructive pulmonary disease (COPD) or asthma, admitted to our division because of exacerbation of their conditions and requiring intensified treatment with corticosteroids, underwent pulmonary function tests, tests of respiratory muscle function, measurement of quadricep strength, and a variety of anthropometric and biochemical measurements. All tests were performed the 10th day after admission. As expected, muscle strength and pulmonary function were interrelated. Surprisingly, the average daily dose of steroids taken in the previous 6 mo, which ranged from 1.4 to 21.3 mg (average 4.3 mg), was significantly related to inspiratory muscle strength (PImax) and a similar tendency was present for expiratory muscle strength (PEmax). Multiple regression analysis of the relationship between PImax and quadriceps force (QF) and steroid dose revealed that the average daily dose independently explained 32% of the variance in PImax and up to 51% of the variance in QF. These relationships were independent of the degree of bronchial obstruction estimated by percentage predicted FEV1. Other significant determinants were age, sex, and COPD for PImax and age, sex, and body weight for QF. The present study demonstrates that in patients with COPD or asthma, respiratory and peripheral muscle strength and steroid treatment are interrelated despite the relatively low doses administered. This observation imposes further limitations on the prolonged treatment of chronic airflow obstruction with systemic corticosteroids.