Life-Threatening Hyperkalemia following Low-Dose Trimethoprim-Sulfamethoxazole: A Case Report

An experimental study on the effects of ethanol and folic acid deficiency, alone or in combination, on pregnant Swiss mice

Angiotensin converting enzyme inhibitors improve symptoms and prolong life in congestive heart failure, but the dose in the individual patient is uncertain. A randomized, 48-week, double-blind study was performed to investigate the safety and efficacy of 'high' in comparison to continued 'low' angiotensin converting enzyme inhibitor therapy in severe heart failure. Eighty-three patients (56 +/- 1.1 years; 69 men, 14 women) in New York Heart Association functional class III/IV on digoxin, furosemide and 'low' angiotensin converting enzyme inhibitors (captopril < or = 50 mg.day-1 or enalapril < or = 10 mg.day-1) were included. After a > or = 14 day run-in on 10 mg.day-1 enalapril, digitalis and furosemide, right heart catheterization at rest and exercise was performed. All patients presented with atrial pressure > 10 mmHg and/or pulmonary artery pressure > 35 mmHg, and/or cardiac index < 2.5 l.min-1.m-2 at rest. Patients then received enalapril 5 mg twice daily (n = 42), or 20 mg twice daily (n = 41) in random order. Thus, patients randomized to low doses of enalapril actually had no change in therapy from baseline to 48 weeks. Forty-three patients (52%) completed the study, 19 patients on the low dose and 24 patients on the high dose. Both dosages equally influenced survival with 15 (18%) deaths, eight on low dose and seven on high dose. After 48 weeks, functional capacity by New York Heart Association class improved more on the high dose than on the low dose (P = 0.04). In contrast, alterations in invasive haemodynamic variables at rest and exercise as well as maximal exercise capacity were comparable in both groups. Diastolic blood pressure decreased and the change between both groups was statistically significant (P = 0.01). Changes in plasma creatinine levels did not differ between high and low dose treatment and no patients had to be withdrawn because of deterioration in kidney function. With regard to neurohumoral activity, a tendency to a discrepant response to both treatments was observed with a blunted increase in noradrenaline on high versus low enalapril dose. Thus, high-dose enalapril treatment proved superior to low dose as regards symptomatology in severe heart failure after long-term treatment, despite similar effects on haemodynamics and on maximal exercise capacity.

We report a girl who developed severe and fatal hyperkalemia following rapid and massive blood transfusion during surgery. She was 7-year-old, 20-kg in weight, and received wide resection of the femoral bone with custom prosthesis implant because of malignant femoral osteosarcoma. During the procedure, bleeding was active and profuse and amounted to about 3,000 mL in 4 h, eventuating in shock. Despite rapid transfusion with 15 units of packed red blood cells (RBC) still she remained hypotensive and hypovolemic. When we switched to give her whole blood, actually 100 mL having been given, widening of QRS complex followed immediately by cardiac arrest developed. Cardiopulmonary resuscitation although started at once was unsuccessful. At this juncture, arterial blood gas analysis showed acidosis and severe hyperkalemia (10.3 mmol/L), possibly resulting from transfusion of blood of older storage. The case reminded us once again the importance and necessity of the use of potassium-low blood component (fresh, saline-washed RBCs) in case of massive and rapid blood transfusion especially in pediatric patients with hypovolemia and low cardiac output.

Comparison of low and high dose intracoronary adenosine and acetylcholine in women undergoing coronary reactivity testing: Results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE)

Editor – We would like to comment on an article published by Doi et al.1 The report was based on a review of studies examining the effectiveness of low and high administered doses of radioiodine for the ablation of thyroid remnant among patients with differentiated thyroid cancer. Their analysis was based on a previously published systematic review conducted by Hackshaw et al2 which concluded that there is currently insufficient evidence to reliably say whether a low dose is associated with a lower ablation success rate than a high dose. Doi et al, however, use the same studies to conclude that a low dose is worse, but there are fundamental problems with their analysis and interpretation. First, they combine studies with very different designs into a single meta-analysis producing a relative risk which appears to be precise and highly statistically significant. The relative risk of having a successful ablation in the low dose group compared to the high dose group was 0.73, 95% confidence interval (CI) 0.61–0.81. The 22 studies, on which this particular result is based, are a mixture of cohort studies, retrospective reviews of patient medical records, and randomized trials. It is inappropriate to combine these studies when the observational studies are likely to be affected by inherent biases and confounding, but the randomized trials are not. Indeed, meta-analyses of observational studies need to be interpreted with great care because the effect of potential confounding in each study could be magnified when the studies are combined, thus producing a spuriously precise effect.3 Sixteen of the 22 studies (73%) were observational, so their results will contribute most to the pooled result. The best evidence must come from randomized clinical trials. Second, when their analysis was restricted to the 6 randomized trials (in which no comparison was based on more than 150 patients in total), the pooled relative risk was 0.68 (95% CI 0.43–1.07), which was not statistically significant (P-value of 0.093). The correct interpretation is that, while there is some evidence of a lower ablation rate when using a low dose, the effect could be due to chance because the CI includes the no-effect value and P >0.05 (i.e., there could be no true difference). However, no comment was made on this. Third, the dose level that defines ‘low’ and ‘high’ differs greatly between these trials. For example, a low dose could be 30 or 50 mCi (a difference of two-thirds), and a high dose could be 50 or 100 mCi (a difference of two-fold). Because of this, it is best to not combine all the trials to produce a single relative risk. Once these considerations have been taken into account, there is no analysis that allows firm conclusions to be made about the comparison of low and high dose radioiodine in treating differentiated thyroid cancer. While some clinicians prefer to administer a high dose at present, it is misleading to rule out the use of a low dose based on current evidence. There are clear potential advantages, such as less time spent in isolation in hospitals and lower risk of future second malignancies.2 What is needed is a large randomized trial, and there are two such trials in progress in the UK and France, each based on several hundred patients.4 These trials will determine with sufficient certainty whether a low dose should be avoided, or could be used instead of a high dose.

Digitalis is the oldest compound in cardiovascular medicine that continues to be used in contemporary clinical practice.1 Evidence supporting the beneficial effects of digoxin on hemodynamic, neurohormonal, and electrophysiological parameters has been accumulated from >200 years of clinical experience and research (Table 1).2 View this table: TABLE 1. Effects of Digoxin Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), and Digitalis Investigators Group (DIG) clinical trials.3–5 It was also approved for the control of ventricular response rate for patients with atrial fibrillation. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function (Class IIa recommendation: weight of evidence/opinion is in favor of usefulness/efficacy), preserved systolic function (Class IIb: usefulness/efficacy is less well established by evidence/opinion), and/or rate control for atrial fibrillation with a rapid ventricular response (Class IIa).6 The new Heart Failure Society of America guidelines for heart failure provide similar recommendations.7 Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, digoxin use is decreasing in patients with heart failure.8 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, only 30% of patients with left ventricular systolic dysfunction were being treated with digoxin before admission. Digoxin was added in only 8% of patients before discharge despite the fact that they had signs and symptoms of heart failure while receiving diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) and β-blockers.9,10 This decrease in digoxin use is likely the result of several factors. …

Comparison of effects of no-, medium-, and high dose dexamethasone in adult cardiac surgery – A post-hoc analysis of the prospective, observational inflacor trial

Introduction: Clostridium difficile is implicated in 15%–25% of all cases of nosocomial antibiotic-associated diarrhea. Current guidelines recommend oral vancomycin 125 mg every six hours as the drug of choice for severe CDI. The recommendation is based on a retrospective analysis showing vancomycin to be superior to oral metronidazole for the treatment of severe disease, as well as data demonstrating no difference in outcomes between low (125 mg) and high (500 mg) dose vancomycin regimens. Despite this, many clinicians frequently prescribe higher doses (250, 500 mg) of oral vancomycin for severe CDI. While historical literature has suggested no benefit to increased doses of vancomycin, such data do not exist in the age of a more hypervirulent strain. Methods: This study evaluated adult patients admitted to four Detroit Medical Center hospitals hours with CDI confirmed by polymerase chain reaction and meeting severe CDI criteria. Patients received oral vancomycin 125mg every 6 hours (low dose), 250mg or 500mg every 6 hours (considered high dose for study purposes). Patients receiving concomitant CDI therapy were excluded. Exposure to concomitant antimicrobials was also collected. Groups were defined: low dose (LD) vs high dose (HD). P-values < 0.05 were considered significant. Results: From July 2010 to July 2012, this study included 137 CDI patients with a mean age of 67 years. LD group included 95 patients and HD group included 42. Baseline characteristics were similar between groups. Length of stay was 12 ± 9.6 LD v 11.8 ± 10.1 days HD, p=0.33. Duration of diarrhea was 4.2 days LD and 4.1 days HD, p=0.72. ICU admission was required in 28% LD patients and 26% HD, p=0.76. A mean of 2 non-CDI antimicrobials were received in 69% LD and 74% HD while on CDI therapy, p=0.61. Overall clinical cure was achieved in 74% LD and 67% HD, p=0.42. The overall mortality rate was not different between groups, 5.3% LD and 2.4% HD, p=0.67. Conclusions: Clostridium difficile is a very prevalent nosocomial infection. Many patients continue to receive concomitant antimicrobials while on CDI therapy. Increasing the dose of oral vancomycin for patients with severe CDI does not improve efficacy.

BackgroundWhile most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.Methods22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.ResultsFP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.Conclusions200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration.

The ACE inhibitor lisinopril is a lysine derivative of enalaprilat, the active metabolite of enalapril. In patients with heart failure, maximum pharmacodynamic effects are produced 6 to 8 hours after administration of the drug and persist for 12 to 24 hours. High doses (32.5 to 35mg, administered once daily) of lisinopril in the Assessment of Treatment with Lisinopril and Survival (ATLAS) study demonstrated clinically important advantages over low doses (2.5 to 5mg, administered once daily) of the drug in the treatment of congestive heart failure. High doses of lisinopril were more effective than low doses in reducing the risk of major clinical events in patients with heart failure treated for 39 to 58 months. Compared with recipients of low doses, those receiving high doses of lisinopril had an 8% lower risk of all-cause mortality (p = 0.128), a 12% lower risk of death or hospitalisation for any reason (p = 0.002) and 24% fewer hospitalisations for heart failure (p = 0.002). These benefits were associated with significant cost savings. In short term (generally 12 weeks' duration) randomised, double-blind, parallel-group, multicentre clinical trials, lisinopril was significantly more effective than placebo and was at least as effective as captopril, enalapril, digoxin and irbesartan at improving symptomatic end-points and clinical status in patients with heart failure. Lisinopril is generally well tolerated by patients with heart failure. In controlled clinical trials, the most common adverse events occurring in recipients of the drug were dizziness, headache, hypotension and diarrhoea. Overall adverse event profiles for patients treated with high or low doses of lisinopril in the ATLAS study were similar. However, high doses of lisinopril used in the ATLAS study were associated with a higher incidence of adverse events, importantly hypotension and worsening renal function; nevertheless, these events were generally well managed by altering the dose of lisinopril or concomitant medications. Furthermore, despite the higher incidence of some adverse events with high doses of lisinopril, the frequency of treatment discontinuations because of adverse events was the same in the high and low dose groups. Lisinopril (when added to diuretics and/or digoxin) provides symptomatic benefits in patients with congestive heart failure. The ATLAS study demonstrated that high doses of lisinopril significantly reduced the risk of the combined end-point of morbidity and mortality compared with low doses of the drug. Importantly, there was no clinically significant decrease in the tolerability of the drug with use of a high dose. Lisinopril is at least as effective and as well tolerated as other members of the ACE inhibitor class for the treatment of congestive heart failure.

Lively debate continues on the nature of the dose-response relationship for the excess risk of cancer following exposure to ionising radiation at low doses and/or low dose rates. Clearly, these are the exposure conditions of principal importance to radiological protection. Presently, for the purposes of radiological protection, the assumption is made that the underlying dose-response relationship is linear-quadratic with no threshold, and that in the low dose and/or low dose rate region this curve can be approximated by a straight line with a gradient half that of the linear relationship which (for cancers other than leukaemia) is appropriate for moderate to high doses received at high dose rates. This, in essence, is the `linear-nonthreshold (LNT) dose-response model' referred to in the title of NCRP Report No 136.

Renin-angiotensin system blockade: to what extent?

Key role of the molecular autopsy in sudden unexpected death

PI3K inhibitors have shown promise for the treatment of anti-estrogen-resistant breast cancers. Current PI3K inhibitor treatment regimens incompletely and transiently inhibit the pathway in carcinomas, and are accompanied by adverse effects in patients. We found that different periods of PI3K inhibition (12, 24, 36 h) potentiated anti-estrogen-induced apoptosis and inhibition of proliferation to similar extents in cultured ER+ cells. We thus hypothesized that short-term, complete inhibition of PI3K will have a greater anti-tumor effect and reduced systemic toxicity than chronic, partial inhibition. Pharmacokinetic analysis of the orally available pan-PI3K inhibitor GDC-0941 at low (100 mg/kg) and high (800 mg/kg) doses in mice revealed that plasma levels peaked after 15-30 min. (18.6 uM and 20.7 uM, respectively), and decreased to a plateau phase after 1 h that was maintained for 8 h with low dose (6.8-10.7 uM) and 23 h with high dose (7.9-15 uM). We performed MCF-7 tumor pharmacokinetic analyses with low and high doses, and with 2 low doses administered 12 hours apart. Tumor GDC-0941 levels peaked after 9 h (1.6 uM with low-dose; 16.9 uM with high-dose). The second low dose increased tumor drug concentrations to 3.2 uM at 9 h after the second dose, compared to 1.6 uM at 9 h after the first dose. After 48 h, tumor drug concentrations decreased to 0 uM with low dose, and to 4.5 uM with high dose. Mice bearing MCF-7 tumors were treated with fulvestrant (5 mg/wk). Three days later, GDC-0941 was administered to assess pharmacodynamic effects. Phospho-AKT and -S6 levels (markers of PI3K and mTORC1 activities, respectively) were maximally suppressed after 1 h and 3 h of high- and low-dose treatments, respectively, returned to baseline within 16 h after low-dose treatment, and remained suppressed for 36 h following high-dose treatment. PARP cleavage (marker of apoptosis) occurred within 1 h and 3 h of high- and low-dose treatments, and increased over time. Re-treatment of mice with low-dose GDC-0941 after 12 h induced continued inhibition of PI3K and mTORC1 for 9-12 h, suggesting that BID low-dose treatment may be sufficient to continually inhibit PI3K. Comparison of high-dose and low-dose BID tumors showed that these treatments induced similar amounts of PI3K inhibition and PARP cleavage at 21-24 h. Mice bearing MCF-7 or fulvestrant-resistant T47D/FR tumors were treated with vehicle, fulvestrant, GDC-0941 (100 mg/kg QD 5 d/wk; 100 mg/kg BID 3 d/wk, 800 mg/kg QW), or combinations of fulvestrant and GDC-0941. Drug combinations induced tumor regression, fulvestrant did not affect tumor growth, high-dose GDC-0941 QW slowed tumor growth, and low-dose GDC-0941 QD or BID appreciably inhibited tumor growth. However, there was no significant difference among doses and schedules of GDC-0941 in the context of a fulvestrant backbone in either tumor model. These data suggest that transient/metronomic (QD, BID) and chronic/infrequent (QW) PI3K inhibition may provide similar anti-tumor efficacy in combination with an anti-estrogen. However, these tumor growth data conflict with cell fate data indicating that high-dose GDC-0941 induced much more apoptosis than low-dose GDC-0941. Ongoing studies will reveal how different schedules of PI3K inhibition shape tumor biology. Citation Format: Wei Yang, Jennifer R Bean, Lloye Dillon, Laurent Salphati, Jodie Pang, Xiaolin Zhang, Michelle Nannini Pepe, Todd W Miller. Understanding pharmacodynamics and consequences of PI3K inhibition in ER+ breast tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-20-03.