Similarities and distinctions between acetazolamide and sodium–glucose cotransporter 2 inhibitors in patients with acute heart failure: Key insights into ADVOR and EMPULSE

Both acetazolamide and sodium–glucose cotransporter 2 (SGLT2) inhibitors block sodium reabsorption in the proximal renal tubule primarily through inhibition of sodium–hydrogen exchanger isoform 3 (NHE3), but neither SGLT2 inhibitors nor acetazolamide produce a sustained natriuresis due to compensatory upregulation of sodium reabsorption at distal nephron sites. Nevertheless, acetazolamide and SGLT2 inhibitors have been used as adjunctive therapy to loop diuretics in states where NHE3 is upregulated, e.g. acute heart failure. Two randomized controlled trials have been carried out with acetazolamide in acute heart failure (DIURESIS-CHF and ADVOR). In ADVOR, acetazolamide improved physical signs of fluid retention, but this finding could not be explained by the modest observed diuretic effect. Acetazolamide did not produce a natriuresis in the DIURESIS-CHF trial, and in ADVOR, immediate effects on symptoms and body weight were not reported, and the drug had no effect on morbidity or mortality after 90 days. Three randomized controlled trials have been carried out with empagliflozin (EMPAG-HF, EMPA-RESPONSE-AHF and EMPULSE) in acute heart failure. The EMPULSE trial did not report effects on diuresis or in changes in physical signs of congestion during the first week of treatment, but in EMPAG-HF and EMPA-RESPONSE-AHF, empagliflozin had no effect of dyspnoea, urinary sodium excretion or body weight during the first 4 days. In the EMPULSE trial, empagliflozin improved health status at 15 days and reduced the risk of worsening heart failure events at 90 days, but these effects are similar in magnitude and time course to the early statistical significance on the risk of heart failure hospitalizations achieved within 14–30 days in the major trials of SGLT2 inhibitors in patients with chronic heart failure. Neurohormonal inhibitors produce this early effect in the absence of a diuresis. Additionally, in numerous randomized controlled trials, in-hospital diuretic intensification has not reduced the risk of major heart failure events, even when treatment is sustained. These findings, taken collectively, suggest that any immediate diuretic effects of acetazolamide and SGLT2 inhibitors in acute heart failure are not likely to influence the short- or long-term clinical course of patients.     

Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation

Aims

Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF.

Methods and results

In this pre-defined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m²/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF.

Conclusions

In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF.     

Long-term survival and state of health after paediatric intensive care

Survival and state of health were assessed one year after discharge in 468 children admitted to an intensive care unit (ICU). ICU mortality was 7.5%, cumulative hospital mortality 8.3%, and one year mortality 10.5%. An established six domain health status classification was used, comprising sensation, mobility, emotion, cognition, self care, and pain to determine the presence, type, and severity of chronic health impairment. This classification has not been validated for infants, who were therefore excluded. After one year, of the 254 patients eligible for analysis, 80 (31.5%) had no overall health impairment (no affected domains) preceding admission; of these, 11 had died in ICU and 69 were long-term survivors, among whom 45 recovered to perfect health. There was overall health impairment (> or = 1 affected domain) preceding admission in 174 of 254 patients (68.5%). However, after one year, overall state of health was improved or equal to the preadmission state in 164 of 226 survivors (72.6%). In domain-specific health, the proportion improving or remaining unchanged varied from 77.9% (emotional functions) to 89.4% (mobility and pain). Consequently, despite the large number with health impairment before admission, cumulative one year survival was favourable and health status in three quarters of the population was preserved.     

Three- and four-year cognitive outcome in children with noncortical brain tumors treated with whole-brain radiotherapy.

Cognitive function and school achievement were studied prospectively over 3 to 4 years in 19 children treated for brain tumors with whole-brain radiotherapy; 14 of 19 also received adjuvant chemotherapy. For the group as a whole, mean IQ fell from a baseline of 104 to 92 at follow-up (p < 0.01). Age was inversely correlated with change in IQ over time (r = 0.71; p < 0.001). Children younger than 7 years at diagnosis had a mean IQ loss of 27 points, while children over 7 years at diagnosis showed no significant decrease in IQ. Decline in IQ occurred between baseline and year 2 of follow-up; none could be documented between years 2 and 4. All children younger than 7 years at diagnosis were receiving special education at follow-up; 50% of the children over 7 years at diagnosis were receiving supplemental educational services.     

Granulocyte-macrophage colony-stimulating factor and interleukin-3 mRNAs are produced by a small fraction of blood mononuclear cells

Northern blot analysis has identified granulocyte macrophage colony stimulating factor (GM-CSF) mRNA in monocytes and both GM-CSF and interleukin-3 (IL-3) mRNA in lymphocytes. However, these results have not addressed whether all cells or a subset of the population is capable of hematopoietic growth factor (HGF) production. To resolve this question, we applied in situ hybridization of radiolabeled antisense RNA probes to centrifuged preparations of total blood mononuclear cells (BMCs) and fractionated lymphocyte subpopulations. Without stimulation, no circulating cells expressed detectable levels of GM-CSF or IL-3 mRNA. On stimulation of BMCs with phorbol myristate acetate (PMA) and phytohemagglutinin or PMA and the calcium ionophore ionomycin, approximately 5% expressed GM-CSF mRNA and approximately 1% IL-3 mRNA. Control sense probes produced no labeled cells. To determine the subsets of lymphocytes capable of GM-CSF and IL-3 expression, BMCs were fractionated by FACS into CD8+ and CD4+ lymphocyte subsets and CD16+ (NK) cells. The unfractionated cells and cell fractions were then stimulated with PMA and ionomycin. Results demonstrated that 3% to 5% of the CD16+, CD8+, and CD4+ lymphocytes produced GM-CSF mRNA. However, the number of IL-3 mRNA-positive cells in the FACS-sorted subsets was greatly reduced (0.02% to 0.05%) as compared with the unseparated cells (1%). Treatment of BMCs with high-dose interleukin-2 (IL-2) for 1 week followed by PMA plus ionomycin resulted in a lymphocyte population in which 50% and 3% of cells expressed GM-CSF and IL-3 mRNA, respectively. Thus, GM-CSF and IL-3 mRNA expression in T cells and NK cells is restricted to a small fraction of cells that can be greatly expanded by IL-2 stimulation. These results suggest a possible physiologic mechanism for increasing HGF production by circulating lymphocytes.     

Nitrate and N-nitrosoproline excretion in two Italian regions with contrasting rates of gastric cancer: the role of nitrate and other factors in endogenous nitrosation.

Exposure to nitrate and propensity for endogenous nitrosation were examined in 80 healthy males, aged 25-40 years, residing in areas of Italy with long-standing high (Florence) and low (Cagliari) rates of gastric cancer. Nitrate exposure was assessed by measurement of urinary nitrate excretion over 12 hr, and endogenous nitrosation was assessed using the N-nitrosoproline test (NPRO-test). Our hypothesis was whether the geographic variation in cancer rate correlated with nitrate exposure or nitrosating ability. Exposure to background sources of NPRO was significantly higher in the high-risk subjects (phi = 0.04) whereas no differences were found in exposure to nitrate or in urinary NPRO levels after L-proline loading (test NPRO levels). The regional difference in test NPRO was almost completely accounted for by background NPRO exposure. Examination of individual rather than grouped data revealed that exposure to nitrate was a major factor in NPRO formation. No other factors studied (age, dietary-questionnaire-assessed intake of anti-oxidant vitamins) had a significant effect. Geographical variation in gastric cancer risk did not, therefore, correlate with either nitrate exposure or propensity for endogenous nitrosation of L-proline.     

DELAY IN THE DIAGNOSIS OF OSTEOMYELITIS PUBIS

SUMMARY The pubis is an uncommon site for osteomyelitis, which fact may contribute to difficulty in establishing the diagnosis. Two cases of osteomyelitis pubis in children are presented in which the diagnosis and definitive treatment were delayed.