Core competencies in critical care for general medical practitioners in South Africa: A Delphi study.

Background: Despite a high burden of disease that requires critical care services, there are a limited number of intensivists in South Africa (SA). Medical practitioners at district and regional public sector hospitals frequently manage critically ill patients in the absence of intensivists, despite these medical practitioners having had minimal exposure to critical care during their undergraduate training. Objectives: To identify core competencies in critical care for medical practitioners who provide critical care services at public sector hospitals in SA where intensivists are not available to direct patient management. Methods: A preliminary list of core competencies in critical care was compiled. Thereafter, 13 national and international experts were requested to achieve consensus on a final list of core competencies that are required for critical care by medical practitioners, using a modified Delphi process. Results: A final list of 153 core competencies in critical care was identified. Conclusion: The core competencies identified by this study could assist in developing training programmes for medical practitioners to improve the quality of critical care services provided at district and regional hospitals in SA. Contribution of the study: The study provides consensus on a list of core competencies in critical care that non-intensivist medical practitioners managing critically ill patients in healthcare settings in South Africa, especially where intensivists are not readily available, should have. The list can form the core content of training programmes aimed at improving critical care competence of general medical practitioners, and in this way hopefully improve the overall outcomes of critically ill patients in South Africa.

Iatrogenic blood loss in critical care: A prospective observational study conducted at Universitas Academic Hospital in the Free State Province, South Africa.

Background: Prevention of iatrogenic blood loss is an essential component of patient blood management (PBM) in intensive care units (ICUs). The amount of iatrogenic blood loss from diagnostic phlebotomy in the ICUs at Universitas Academic Hospital, Free State Province, South Africa, is unknown. Objectives: To quantify diagnostic phlebotomy volumes, and volumes submitted in excess for diagnostic testing in the ICU. Methods: We conducted a prospective descriptive observational study on adults who were admitted to ICUs at a single centre over a period of 14 days. The weight of each filled phlebotomy tube was calculated using the specific gravity of blood and averages of empty phlebotomy tubes, establishing the total volume. Results: Data from 59 participants with a median length of stay at the ICU of 3 days were analysed. The median phlebotomy volume was 7.0 mL day and 13.6 mL/ICU admission. The volume of blood required for analysis daily and ICU admission was 0.7 mL and 2.2 mL, respectively. The median phlebotomy volume in excess of the amount required for analysis daily and ICU admission was 5.05 mL and 12.11 mL, respectively. Conclusion: While the median excess daily phlebotomy volume in this present study may seem insignificant and underestimating the true excess of phlebotomy volume, interventions to reduce phlebotomy volumes and development of a PBM guideline for appropriate phlebotomy volumes and preventing wastage of patients' blood in the ICU is required. Contributions of the study: We determined blood volume requirements for laboratory instrumentation, which allows phlebotomists to be cognisant of the true requirements for diagnostic tests to be undertaken accurately. We established diagnostic blood loss volumes in critical care units at a tertiary hospital in South Africa and we advocate for the introduction of patient blood management practice guidelines at local institutions.

South African guidelines on the determination of death.

Death is a medical occurrence that has social, legal, religious and cultural consequences requiring common clinical standards for its diagnosis and legal regulation. This document compiled by the Critical Care Society of Southern Africa outlines the core standards for determination of death in the hospital context. It aligns with the latest evidence-based research and international guidelines and is applicable to the South African context and legal system. The aim is to provide clear medical standards for healthcare providers to follow in the determination of death, thereby promoting safe practices and high-quality care through the use of uniform standards. Adherence to such guidelines will provide assurance to medical staff, patients, their families and the South African public that the determination of death is always undertaken with diligence, integrity, respect and compassion, and is in accordance with accepted medical standards and latest scientific evidence. The consensus guidelines were compiled using the AGREE II checklist with an 18-member expert panel participating in a three-round modified Delphi process. Checklists and advice sheets were created to assist with application of these guidelines in the clinical environment (https://criticalcare.org.za/resource/death-determination-checklists/). Key points • Brain death and circulatory death are the accepted terms for defining death in the hospital context. • Death determination is a clinical diagnosis which can be made with complete certainty provided that all preconditions are met. • The determination of death in children is held to the same standard as in adults but cannot be diagnosed in children <36 weeks' corrected gestation. • Brain-death testing while on extra-corporeal membrane oxygenation is outlined. • Recommendations are given on handling family requests for accommodation and on consideration of the potential for organ donation. • The use of a checklist combined with a rigorous testing process, comprehensive documentation and adequate counselling of the family are core tenets of death determination. This is a standard of practice to which all clinicians should adhere in end-of-life care.

South African guidelines on the determination of death.

Summary: Death is a medical occurrence that has social, legal, religious and cultural consequences requiring common clinical standards for its diagnosis and legal regulation. This document compiled by the Critical Care Society of Southern Africa outlines the core standards for determination of death in the hospital context. It aligns with the latest evidence-based research and international guidelines and is applicable to the South African context and legal system. The aim is to provide clear medical standards for healthcare providers to follow in the determination of death, thereby promoting safe practices and high-quality care through the use of uniform standards. Adherence to such guidelines will provide assurance to medical staff, patients, their families and the South African public that the determination of death is always undertaken with diligence, integrity, respect and compassion, and is in accordance with accepted medical standards and latest scientific evidence. The consensus guidelines were compiled using the AGREE II checklist with an 18-member expert panel participating in a three-round modified Delphi process. Checklists and advice sheets were created to assist with application of these guidelines in the clinical environment (https://criticalcare.org.za/resource/death-determination-checklists/). Key points: Brain death and circulatory death are the accepted terms for defining death in the hospital context.Death determination is a clinical diagnosis which can be made with complete certainty provided that all preconditions are met.The determination of death in children is held to the same standard as in adults but cannot be diagnosed in children <36 weeks' corrected gestation.Brain-death testing while on extra-corporeal membrane oxygenation is outlined.Recommendations are given on handling family requests for accommodation and on consideration of the potential for organ donation.The use of a checklist combined with a rigorous testing process, comprehensive documentation and adequate counselling of the family are core tenets of death determination. This is a standard of practice to which all clinicians should adhere in end-of-life care.

Real-time selected ion flow tube mass spectrometry to assess short- and long-term variability in oral and nasal breath.

Breath-based non-invasive diagnostics have the potential to provide valuable information about a person's health status. However, they are not yet widely used in clinical practice due to multiple factors causing variability and the lack of standardized procedures. This study focuses on the comparison of oral and nasal breathing, and on the variability of volatile metabolites over the short and long term. Selected ion flow tube mass spectrometry (SIFT-MS) was used for online analysis of selected volatile metabolites in oral and nasal breath of 10 healthy individuals five times in one day (short-term) and six times spread over three weeks (long-term), resulting in nearly 100 breath samplings. Intra-class correlation coefficients (ICCs) were used to assess short- and long-term biological variability. Additionally, the composition of ambient air was analyzed at different samplings. The selected volatiles common in exhaled breath were propanol, 2,3-butanedione, acetaldehyde, acetone, ammonia, dimethyl sulfide, isoprene, pentane, and propanal. Additionally, environmental compounds benzene and styrene were analyzed as well. Volatile metabolite concentrations in ambient air were not correlated with those in exhaled breath and were significantly lower than in breath samples. All volatiles showed significant correlation between oral and nasal breath. Five were significantly higher in oral breath compared to nasal breath, while for acetone, propanal, dimethyl sulfide, and ammonia, concentrations were similar in both matrices. Variability depended on the volatile metabolite. Most physiologically relevant volatiles (acetone, isoprene, propanol, acetaldehyde) showed good to very good biological reproducibility (ICC > 0.61) mainly in oral breath and over a short-term period of one day. Both breathing routes showed relatively similar patterns; however, bigger differences were expected. Therefore, since sampling from the mouth is practically more easy, the latter might be preferred.

Four-oil intravenous lipid emulsion effect on plasma fatty acid composition, inflammatory markers and clinical outcomes in acutely ill patients: A randomised control trial (Foil fact).

BACKGROUND AND AIMS: Data in critically ill patients on the effect of intravenous lipid emulsions (LEs), containing omega-3 polyunsaturated fatty acids (PUFAs), in parenteral nutrition (PN) are scarce and conflicting. This study compared the effects of a four-oil LE (30% soybean oil, 30% medium-chain triglycerides, 25% olive oil and 15% fish oil (FO)) (SMOFlipid®) to those of a 100% soybean oil-based LE in critically ill adult intensive care unit (ICU) patients. METHODS: In this double-blind, randomised study, patients (n = 75) predicted to need PN for more than 5 days were randomised to receive either a four-oil LE (Study Group (SG)) or a 100% soybean oil LE (Control Group (CG)). Isocaloric, isonitrogenous PN was administered continuously for 5 days. FO was provided at a dose of 0.09-0.22 g/kg body weight. Measurements included biochemical parameters and sequential organ failure assessment (SOFA) score daily and plasma total phospholipid fatty acids (FAs) and cytokine levels on days 1, 3, 6. Days on mechanical ventilation, length of stay and mortality were also recorded. ANOVA was used to compare response variables between the two groups over the time and Pearson correlation was used to measure relationships between continuous variables. RESULTS: 68 patients completed the study (n = 35 SG, n = 33 CG), with male predominance (66% SG, 56% CG). Average age was 60.8 ± 13.9 years (SG) versus 55.7 ± 14.8 (CG) (p = 0.143). The majority were surgical admissions (85% SG versus 91% CG) followed by medical. Plasma phospholipid oleic acid (p = 0.022) and alpha-linolenic acid (p<0.0005) increased in both groups. In the SG, plasma phospholipid EPA and DHA increased (both p<0.001), whereas the omega-6:omega-3 PUFA (n-6:n-3 PUFA) ratio decreased (p < 0.001). Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin decreased in both treatment groups. Considering only the change from day 1 to day 6 there was a bigger decrease in AST, ALT and bilirubin levels in the SG. Concentrations of TNF-α decreased from day 1 to day 6 in the SG, whereas they increased in the CG, but the change was not statistically significant (p = 0.112). A significant negative correlation was found between EPA provision on day 3 and the SOFA score (r = -0.4047, p = 0.018). Days on mechanical ventilation (1.24 ± 0.83 days in SG versus 0.88 ± 1.63 days in CG, p = 0.385) and ICU LOS (9.5 ± 7.09 days in SG versus 10.7 ± 7.6 days in CG, p = 0.490) were not different between groups. CONCLUSION: PN containing a four-oil LE increased plasma EPA and DHA, decreased n-6:n-3 PUFA ratio, and was safe and well tolerated. The negative relationship between day 3 EPA and SOFA score seems promising, but EPA intake and effects may have been diluted by enteral nutrition which was started in more than half of patients on day 4. There was no significant difference in terms of other biochemical measurements, SOFA score, length of ICU stay and mortality. More research is needed in this patient population, particularly regarding dose, duration and timing of FO and the effects on clinical outcomes.

Airflow distribution with manual hyperinflation as assessed through gamma camera imaging: a crossover randomised trial.

OBJECTIVES: Manual hyperinflation (MHI) has been shown to improve lung compliance, reduce airway resistance, and enhance secretion removal and peak expiratory flow. The aims of this study were to investigate whether there is a difference in airflow distribution through patients' lungs when using the Laerdal and Mapleson-C circuits at a set level of positive end-expiratory pressure (PEEP), and to establish whether differences in lung compliance and haemodynamic status exist when patients are treated with both these MHI circuits. DESIGN: Crossover randomised controlled trial. SETTING: Adult multidisciplinary intensive care unit (ICU) at an academic hospital. PARTICIPANTS: Fifteen adult patients were recruited and served as their own controls. INTERVENTION: In the Nuclear Medicine Department, MHI with PEEP 7.5 cmH(2)O was performed in the supine position (Day 1) with either Laerdal or Mapleson-C circuits, in a random order, while technetium-99m (Tc-99m) aerosol was administered and images were taken with a gamma camera. Changes in heart rate (HR), mean arterial pressure (MAP) and dynamic lung compliance (C(D)) were documented at baseline, immediately after return to ICU, and 10, 20 and 30 minutes after return to ICU. The alternative circuit was used on Day 2. RESULTS: Tc-99m deposition was greater in the right lung field (62% and 63% for Laerdal and Mapleson-C circuits, respectively) than the left lung field (38% and 37%, respectively) for all patients, and least deposition occurred in the left lower segments (6% and 6%, respectively). No differences in Tc-99m deposition in the lungs, HR, MAP or C(D) were noted between the two MHI circuits. CONCLUSION: Airflow distribution through patients' lungs was similar when the Laerdal and Mapleson-C MHI circuits were compared using a set level of PEEP in the supine position.

The predictive value of diagnostic sonography for the effectiveness of conservative treatment of tennis elbow.

OBJECTIVE: Tennis elbow is a common complaint. Several treatment strategies have been described, but an optimal strategy has not been identified. Sonographic imaging as a predictive factor has never been studied. The aim of our study was to determine the value of sonographic findings in predicting response to conservative therapy for tennis elbow. This was done in a randomized controlled trial in which the effectiveness of a brace only, physical therapy only, and a combination of both were compared. SUBJECTS AND METHODS: Patients with tennis elbow complaints were randomized. Sonography was performed before randomization in 57 patients. Outcome measures at 6 weeks' follow-up were success rate and decrease in pain (scale, 0-100). Data were analyzed using an intention-to-treat analysis. RESULTS: In only 75% of the imaged patients, sonographic abnormalities were identified and the clinical diagnosis could thus be confirmed. The following entities were identified: hypo- and hyperechogenicity, swelling, calcification, bursitis, enthesopathy, and tendinosis. The positive predictive value of sonography for the different entities varied between 0.78 and 0.82, and the negative predictive value ranged between 0.23 and 0.71. Predictive value was studied by subgroups of sonographic findings: hypoechoic, swelling present, enthesopathy, any entity present, and no entity present. We found no significant differences among the subgroups for either success rate (range, 40-54%) or mean decrease in pain (range, 16-28 percentage points). CONCLUSION: No predictive value of sonography for the detection of abnormalities was identified in this study. Its diagnostic capability showed limited value. However, limitations in this study necessitate drawing definitive conclusions with care.

Activation of heterotrimeric G-protein signaling by a ras-related protein. Implications for signal integration.

Utilizing a functional screen in the yeast Saccharomyces cerevisiae we identified mammalian proteins that activate heterotrimeric G-protein signaling pathways in a receptor-independent fashion. One of the identified activators, termed AGS1 (for activator of G-protein signaling), is a human Ras-related G-protein that defines a distinct subgroup of the Ras superfamily. Expression of AGS1 in yeast and in mammalian cells results in specific activation of Galpha(i)/Galpha(o) heterotrimeric signaling pathways. In addition, the in vivo and in vitro properties of AGS1 are consistent with it functioning as a direct guanine nucleotide exchange factor for Galpha(i)/Galpha(o). AGS1 thus presents a unique mechanism for signal integration via heterotrimeric G-protein signaling pathways.

Characterization of endogenous APP processing in a cell-free system.

We have developed a simple in vitro assay using tissue homogenates that allows detection and characterization of several endogenous proteolytic activities which convert Alzheimer's amyloid precursor protein (APP) to the smaller, carboxy-terminal fragments, postulated to be intermediates in the formation of ß-amyloid peptide (Aß). Incubation at 37°C results in the degradation of transmembrane APP and formation of a mixture of carboxy-terminal containing peptides with mass values of 9-12 kDa. Epitope mapping and electrophoretic comparison with a truncated APP standard showed one of these peptides to contain the entire Aß sequence. Analysis of pH dependence shows that formation of this carboxy-terminal product as well as another fragment, that is the likely product of 'secretase' activity, requires acidic pH. This suggests that cleavage of full-length APP to secreted forms may take place in an acidic intracellular compartment.

Evaluation of cathepsins D and G and EC 3.4.24.15 as candidate beta-secretase proteases using peptide and amyloid precursor protein substrates.

No single protease has emerged that possesses all the expected properties for beta-secretase, including brain localization, appropriate peptide cleavage specificity, and the ability to cleave amyloid precursor protein exactly at the amino-terminus of beta-amyloid peptide. We have isolated and purified a brain-derived activity that cleaves the synthetic peptide substrate SEVKMDAEF between methionine and aspartate residues, as required to generate the amino-terminus of beta-amyloid peptide. Its molecular size of 55-60 kDa and inhibitory profile indicate that we have purified the metalloprotease EC 3.4.24.15. We have compared the sequence specificity of EC 3.4.24.15, cathepsin D, and cathepsin G for their ability to cleave the model peptide SEVKMDAEF or related peptides that contain substitutions reported to modulate beta-amyloid peptide production. We have also tested the ability of these enzymes to form carboxyl-terminal fragments from full-length, membrane-embedded amyloid precursor protein substrate or amyloid precursor protein that contains the Swedish KM --> NL mutation. The correct cleavage was tested with an antibody specific for the free amino-terminus of beta-amyloid peptide. Our results exclude EC 3.4.24.15 as a candidate beta-secretase. Although cathepsin G cleaves the model peptide correctly, it displays poor ability to cleave the Swedish KM --> NL peptide and does not generate carboxy-terminal fragments that are immunoreactive with amino-terminal-specific antiserum. Cathepsin D does not cleave the model peptide or show specificity for wild-type amyloid precursor protein; however, it cleaves the Swedish "NL peptide" and "NL precursor" substrates appropriately. Our results suggest that cathepsin D could act as beta-secretase in the Swedish type of familial Alzheimer's disease and demonstrate the importance of using full-length substrate to verify the sequence specificity of candidate proteases.

The release of Alzheimer's disease beta amyloid peptide is reduced by phorbol treatment.

Amyloid precursor protein (APP) is cleaved predominantly within the beta amyloid peptide (BAP) domain to release a non-amyloidogenic amino-terminal PN2 fragment. Treatment of cells with phorbol dibutyrate, an agent which activates protein kinase C, has been shown to increase the release of an amino-terminal fragment. A panel of mutant APP reporter constructs was expressed in which each of the potential phosphorylation sites located within the cytoplasmic domain of APP was replaced with alanine residues. Phorbol response patterns were unchanged for each of these mutants, suggesting that induced cleavage occurs independently of APP substrate phosphorylation. We find that phorbol (a) increases the release of a PN2 fragment that is consistent with the normal secretase activity, (b) decreases the release of a shorter amino-terminal APP fragment that is cleaved near the amino terminus of BAP, and (c) decreases the release of BAP which was identified based on electrophoretic mobility, epitope mapping, and radio-sequencing. These data demonstrate that pharmacological treatment can reduce the formation of BAP and suggests that protein kinase C activators could be developed as therapeutic agents to block BAP formation.

Release of amino-terminal fragments from amyloid precursor protein reporter and mutated derivatives in cultured cells.

Abnormal proteolytic processing of amyloid precursor protein (APP) is thought to be central to the formation and deposition of beta amyloid peptide in Alzheimer's disease. A putative "secretase" activity normally releases an amino-terminal APP fragment by cleaving APP at residues within the beta amyloid peptide thereby precluding amyloidogenesis. In order to better understand the requirements for APP cleavage by secretase, we have expressed a modified cDNA construct representing the 751-amino acid isoform of APP (APP-REP) and mutated APP-REP proteins in cultured cells. Here, we show that: (a) APP-REP is predominantly associated with membranes; (b) intracellular turnover and processing of APP-REP is similar to that reported for the intact APP protein; (c) secretion appears unaltered by introduction of the glutamate to glutamine mutation found in the APP gene of patients suffering from hereditary cerebral hemorrhage with amyloidosis of Dutch origin; (d) a mutation in which the 18 juxtamembranous amino acids encompassing the secretase site are deleted also allows release of an amino-terminal fragment into the conditioned medium; and (e) kinetics of cleavage of APP-REP and its mutated derivatives are similar. These results indicate that the secretory cleavage of the extracellular amino-terminal fragments of APP-REP can occur in the presence of different novel juxtamembranous amino acid sequences.