Use of point-of-care ultrasound during cardiac arrest in the intensive care unit: A cross-sectional survey.

BACKGROUND: There is growing interest in the use of point-of-care ultrasound during cardiac arrest, but few studies document its use in the intensive care unit. OBJECTIVE: We hypothesised this may reflect a low prevalence of use of point-of-care ultrasound during cardiac arrest or negative attitudes towards its use. We aimed to determine the self-reported prevalence, attitudes towards, and barriers to use of point-of-care ultrasound during cardiac arrest in the intensive care unit. METHODS: We conducted a web-based survey over 3 months (08/08/2022-06/11/2022), of intensive care unit consultants and registrars in Victoria, Australia. Descriptive and mixed-methods analyses of Likert-type and free-text answers were performed. RESULTS: The response rate was 91/398 (22.8%), split evenly between consultants and registrars. There was a broad range of clinical and ultrasound experience. Only 22.4% (22/91) of respondents reported using point-of-care ultrasound 75-100% of the time during their management of cardiac arrest. Respondents rated the value they place in point-of-care ultrasound during cardiac arrest 3 (interquartile range: 3-4) and that of a "skilled operator" 4 ((interquartile range; 4-5) on a 5-point scale. Free-text analysis suggested exclusion of "tamponade" (40/80 [50%] comments) as the most valuable use-case and "skill" as a personal barrier (20/73 [27.4%] comments). Personal and departmental barriers were not rated highly, although registrars perceived "lack of a structured training program" as a barrier. Respondents were equivocal in the value they gave point-of-care ultrasound during cardiac arrest but saw greater value when conducted by a skilled operator. CONCLUSIONS: Point-of-care ultrasound was reported to be infrequently used in cardiac arrest, mostly due to self-perceived skill and lack of a structured training program.

COBRA: COde Blue Retrospective Audit in a metropolitan hospital.

BACKGROUND: Inhospital cardiac arrest (IHCA) is an uncommon but challenging problem. AIMS: To investigate the management and outcomes of IHCA, and to investigate the effect of introducing a medical emergency team (MET) on IHCA prevalence. METHODS: Retrospective medical record review of 176 adult IHCA episodes at Box Hill Hospital, a university-affiliated public hospital in metropolitan Melbourne, from July 2012 to June 2017. Inpatients receiving cardiopulmonary resuscitation for IHCA, in inpatient wards, intensive care unit, cardiac catheterisation laboratory and operating theatres were included. Data collected included demographics, resuscitation management and outcomes. Average treatment effect (ATE) was derived from margins estimates and linear regression fitted to hospital outcome, adjusted for IHCA factors. An exponentially weighed moving average control chart was used to explore IHCA prevalence over time. RESULTS: There were 65.3% of IHCA patients who died in hospital. IHCA prevalence was unchanged after the introduction of a dedicated MET service. Factors associated with higher likelihood of survival to discharge were initial cardiac of rhythm ventricular tachycardia (VT) (ATE 0.10 (95% CI = -0.03 to 0.25)) or ventricular fibrillation (VF) (ATE 0.28 (95% CI = 0.11-0.46)), cardiac monitoring at the time of arrest (ATE 0.06 (95%CI = -0.04 to 0.16)) and time to return of spontaneous circulation (ATE 0.023 (95% CI = 0.015-0.031)). CONCLUSIONS: IHCA is uncommon and is associated with high mortality. IHCA prevalence was unchanged after the introduction of a dedicated MET service. Factors associated with improved survival to hospital discharge were initial rhythm VT or VF, cardiac monitoring and shorter resuscitation times.

Proteinase-activated receptor-2 (PAR2) on blood pressure and electrolyte handling in the late pregnant rat.

NEW FINDINGS: What is the central question of this study? Pregnancy requires marked renal sodium and potassium retention and cumulative plasma volume expansion, in the setting of reduced blood pressure. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in virgin and normal pregnant rats. What is the main finding and its importance? PAR2 expression and sensitivity to activation are increased in pregnancy. This implicates a possible role for PAR2 in supporting the renal/vascular adaptations of pregnancy required for normal maternal plasma volume expansion. ABSTRACT: A healthy pregnancy involves renal and systemic haemodynamic adaptations, which allow renal sodium and potassium retention and cumulative plasma volume expansion, accompanied by a decline in blood pressure attributable to a reduction in the total peripheral vascular resistance. When these adaptations do not occur, pregnancy is compromised. The mechanisms permitting these opposing adaptations are largely unknown. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in female virgin and normal late pregnant (LP) rats. We measured the mRNA expression of PAR2 in the renal cortex, outer medulla and inner medulla of virgin and LP rats using quantitative real-time PCR. We also measured in vivo blood pressure, natriuretic and kaliuretic responses to PAR2-activating peptide (SLIGRL-NH2 ) in anaesthetized virgin and LP rats. We found that PAR2 mRNA was increased in the inner medulla of LP rats. We also found that LP rats had larger decreases in blood pressure and increases in net sodium retention compared with virgin rats. These findings suggest that pregnancy enhances sensitivity to the blood pressure-lowering and sodium-retaining effects of PAR2.

Renal T cell infiltration occurs despite attenuation of development of hypertension with hydralazine in Envigo's female Dahl rat maintained on a low-Na+ diet.

Many studies have suggested that renal T cell infiltration contributes to the pathogenesis of salt-sensitive hypertension. To investigate this mechanism further, we determined T cell profiles in the kidney and lymphoid tissues as a function of blood pressure in the female Envigo Dahl salt-sensitive (SS) rat maintained on low-Na+ (LS) diet. Mean arterial pressure and heart rate were measured by telemetry in SS rats from 1 mo old (juvenile) to 4 mo old. Normotensive salt-resistant (SR) rats were included as controls. Frequencies of T helper (CD4+) cells were greater in the kidney, lymph nodes, and spleen in 4-mo-old hypertensive SS rats compared with normotensive SR animals and SS juvenile rats, suggesting that renal T cell infiltration contributes to hypertension in the SS rat on a LS diet. At 1.5 mo, half of the SS rats were treated with vehicle (Veh), and the rest received hydralazine (HDZ; 25 mg·kg-1·day-1) for 11 wk. HDZ impeded the development of hypertension compared with Veh-treated control rats [mean arterial pressure: 157 ± 4 mmHg in the Veh-treated group (n = 6) vs. 133 ± 3 mmHg in the HDZ-treated group (n = 7), P < 0.001] without impacting T helper cell frequencies in the tissues, suggesting that HDZ can overcome mechanisms of hypertension driven by renal T cell infiltration under the LS diet. Renal frequencies of CD4+CD25+ and CD4+CD25+FoxP3+ regulatory T cells were significantly higher in 4-mo-old hypertensive rats compared with normotensive SR rats and SS juvenile rats, suggesting that these T cell subpopulations play a compensatory role in the development of hypertension. Greater understanding of these T cell populations could lead to new therapeutic targets for treating inflammatory diseases associated with hypertension.

Salt-sensitive (Rapp) rats from Envigo spontaneously develop accelerated hypertension independent of ovariectomy on a low-sodium diet.

Inbred salt-sensitive (SS) rats developed by John Rapp and distributed by Harlan (SS/JrHsd) were shown to model ovariectomy-induced hypertension because on a low-sodium (LS) diet, ovariectomized SS (SS-OVX) animals became hypertensive in contrast to their sham-operated (SS-SHAM) normotensive littermates. After Harlan merged with Envigo in 2015, inconsistencies in the LS normotensive phenotype were reported. To further investigate these inconsistencies, we studied the effects of ovariectomy on SS and salt-resistant (SR) rats purchased from Envigo (SS/JrHsd/Env) between 2015 and 2017. The mean arterial pressure (MAP) in SS rats on a LS diet exceeded 160 mmHg at 7 mo old. Ovariectomy at 3 mo had no detectable effect on MAP from 4 to 7 mo, nor did ovariectomy at 1.5 mo significantly affect MAP at 10 mo in either strain; only strain differences in MAP were observed [MAP: SR-SHAM ( n = 7 rats), 102 ± 3 mmHg; SR-OVX ( n = 6 rats), 114 ± 1 mmHg; SS-SHAM ( n = 7 rats), 177 ± 6 mmHg; SS-OVX ( n = 5 rats), 190 ± 12 mmHg; where P < 0.0001 vs. SR, same ovarian-status for SS-SHAM and SS-OVX, respectively]. Whole genome sequencing revealed more genomic variants of SS/JrHsd/Env, including single nucleotide and insertion deletion polymorphisms and higher heterozygous/homozygous ratios compared with the reference genome, than for SS/JrHsd/Mcwi and SS/Jr rats maintained in Milwaukee, WI and Toledo, OH, respectively, and which still exhibit normal blood pressure on a LS diet. These findings demonstrate that the female SS/JrHsd/Env rat has genetically diverged from the original phenotype, which was normotensive on a LS diet when the ovaries were intact but rapidly developed hypertension when the ovaries were removed. Nonetheless, the SS/JrHsd/Env rat could be a valuable model that complements other animal models of spontaneous hypertension used to investigate mechanisms of essential hypertension.

Renal and colonic potassium transporters in the pregnant rat.

Gestational potassium retention, most of which occurs during late pregnancy, is essential for fetal development. The purpose of this study was to examine mechanisms underlying changes in potassium handling by the kidney and colon in pregnancy. We found that potassium intake and renal excretion increased in late pregnancy while fecal potassium excretion remained unchanged and that pregnant rats exhibited net potassium retention. By quantitative PCR we found markedly increased H+-K+-ATPase type 2 (HKA2) mRNA expression in the cortex and outer medullary of late pregnant vs. virgin. Renal outer medullary potassium channel (ROMK) mRNA was unchanged in the cortex, but apical ROMK abundance (by immunofluorescence) was decreased in pregnant vs. virgin in the distal convoluted tubule (DCT) and connecting tubule (CNT). Big potassium-α (BKα) channel-α protein abundance in intercalated cells in the cortex and outer medullary collecting ducts (by immunohistochemistry) fell in late pregnancy. In the distal colon we found increased HKA2 mRNA and protein abundance (Western blot) and decreased BKα protein with no observed changes in mRNA. Therefore, the potassium retention of pregnancy is likely to be due to increased collecting duct potassium reabsorption (via increased HKA2), decreased potassium secretion (via decreased ROMK and BK), as well as increased colonic reabsorption via HKA2.

Impact of food and the proton pump inhibitor rabeprazole on the pharmacokinetics of GDC-0941 in healthy volunteers: bench to bedside investigation of pH-dependent solubility.

GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria. To investigate the clinical significance of food and pH-dependent solubility on GDC-0941 pharmacokinetics a four-period, two-sequence, open-label, randomized, crossover study was conducted in healthy volunteers. During the fasting state, GDC-0941 was rapidly absorbed with a median Tmax of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median Tmax of 4 h and a modest increase in AUC relative to the fasted state, with an estimated geometric mean ratio (GMR, 90% CI) of fed/fasted of 1.28 (1.08, 1.51) for AUC0-∞ and 0.87 (0.70, 1.06) for Cmax. The effect of rabeprazole (model PPI) coadministration on the pharmacokinetics of GDC-0941 was evaluated in the fasted and fed state. When comparing the effect of rabeprazole + GDC-0941 (fasted) to baseline GDC-0941 absorption in a fasted state, GDC-0941 median Tmax was unchanged, however, both Cmax and AUC0-∞ decreased significantly after pretreatment with rabeprazole, with an estimated GMR (90% CI) of 0.31 (0.21, 0.46) and 0.46 (0.35, 0.61), respectively for both parameters. When rabeprazole was administered in the presence of the high-fat meal, the impact of food did not fully reverse the pH effect; the overall effect of rabeprazole on AUC0-∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the Cmax (estimate of 0.43, with 90% CI, 0.37, 0.50). The results of the current investigations emphasize the complex nature of physicochemical interactions and the importance of gastric acid for the dissolution and solubilization processes of GDC-0941. Given these findings, dosing of GDC-0941 in clinical trials was not constrained relative to fasted/fed states, but the concomitant use of ARAs was restricted. Mitigation strategies to limit the influence of pH on exposure of molecularly targeted agents such as GDC-0941 with pH-dependent solubility are discussed.

Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development.

Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered clinical candidates that had available structures, the pKa's and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an "ARA-hypochlorhydric" pH of 4. Taking calculated pKa's and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. More than one-quarter (28%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, nearly three-quarters (73%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, gastrointestinal stromal tumor (GIST)). These data strongly suggest that with the clinical development of ARA-DDI-susceptible cancer therapeutics will come continued challenges for drug-development scientists, oncologists, and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes.

Three financial strategies.

The purpose of this article is to identify financial strategies that are truly effective. The principal research questions include whether specific dialysis cost reductions can be implemented without adversely affecting other operating costs or clinical outcomes. The regression analysis involves 120 months of data, 1990 to 1999, from each of six dialysis centers. Financial data include both operating and capital costs. Severity-adjusted hospitalizations are used as the measure of clinical outcomes. The results indicate that three financial strategies are effective in reducing long-term sustainable costs while preserving patient care quality. First, some adjustments in cost mix can achieve sustainable savings over time. However, the relative lack of substitutability among resources and their cost stickiness limit this strategy. Second, institutional experience results in operating efficiencies and cost reductions. In a stable and mature environment, however, managers may not be able to preserve these savings through improved operational efficiencies. Third, clinic managers can reduce their costs when they avoid episodic clinical complications. This strategy may not be sustainable, of course, as hospitals find their revenues constrained when providing acute care services. Contrary to our expectations, we did not find that reducing labor costs was an effective financial strategy. Moreover, we did not find that reducing indirect costs was an effective financial strategy, although the specific 10-year period of this study could be unique in producing this result, and additional research could produce evidence that a strategy of reducing occupancy or other indirect costs is one with significant potential.

Identifying cost management strategies in dialysis clinics: sustainable savings with positive outcomes.

OBJECTIVES: To examine whether cost management strategies are used in a revenue-constrained environment without compromising clinical effectiveness. STUDY DESIGN: Cross-sectional analysis of monthly cost and acuity-adjusted hospitalization data. METHODS: This research included longitudinal regression analyses involving 10 years of data, 1990 through 1999, from each of 6 dialysis centers. Two sets of regression models were used: one set examined cost interactions and cost trends (P < or = .001); the second set examined clinical outcomes (P < or = .001). Four cost management strategies were examined: (1) selective reductions in targeted cost categories, (2) cost reductions through improved efficiencies, (3) cost avoidance by shifting responsibilities to external parties, and (4) uniform reductions across all cost categories. RESULTS: Managers appeared to have limited opportunity to selectively or uniformly reduce costs because of cost "stickiness" and minimal resource substitutability. Improvements in operational efficiencies and cost shifting to external parties occurred. Over time, however, realized efficiencies increased at a decreasing rate, whereas cost shifting actually declined. Contrary to prior hospital studies, these results indicate significant economies of scale. No statistical correlation was found to indicate that the physician/clinic management teams' use of cost reduction strategies affected acuity-adjusted hospitalizations of dialysis patients. CONCLUSIONS: Strategic models that include both financial and outcomes data can enable healthcare managers to predict both positive and negative results of cost management proposals. These models can help identify aspects of an organization's cost structure that affect sustainable cost savings: cost stickiness, cost substitutability, institutional experience, realized operational improvements, and economies of scale.