Lam Minh Yen

Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial

BACKGROUND The most common cause of death in individuals with severe tetanus in the absence of mechanical ventilation is spasm-related respiratory failure, whereas in ventilated patients it is tetanus-associated autonomic dysfunction. Our aim was to determine whether continuous magnesium sulphate infusion reduces the need for mechanical ventilation and improves control of muscle spasms and autonomic instability. METHODS We did a randomised, double blind, placebo controlled trial in 256 Vietnamese patients over age 15 years with severe tetanus admitted to the Hospital for Tropical Medicine, Ho Chi Minh City, Vietnam. Participants were randomly assigned magnesium sulphate (n=97) or placebo solution (n=98) intravenously for 7 days. The primary outcomes were requirement of assisted ventilation and of drugs to control muscle spasms and cardiovascular instability within the 7-day study period. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN74651862. FINDINGS No patients were lost to follow-up. There was no difference in requirement for mechanical ventilation between individuals treated with magnesium and those receiving placebo (odds ratio 0.71, 95% CI 0.36-1.40; p=0.324); survival was also much the same in the two groups. However, compared with the placebo group, patients receiving magnesium required significantly less midazolam (7.1 mg/kg per day [0.1-47.9] vs 1.4 mg/kg per day [0.0-17.3]; p=0.026) and pipecuronium (2.3 mg/kg per day [0.0-33.0] vs 0.0 mg/kg per day [0.0-14.8]; p=0.005) to control muscle spasms and associated tachycardia. Individuals receiving magnesium were 4.7 (1.4-15.9) times less likely to require verapamil to treat cardiovascular instability than those in the placebo group. The incidence of adverse events was not different between the groups. INTERPRETATION Magnesium infusion does not reduce the need for mechanical ventilation in adults with severe tetanus but does reduce the requirement for other drugs to control muscle spasms and cardiovascular instability.

High prevalence of plasmid-mediated quinolone resistance determinants in commensal members of the Enterobacteriaceae in Ho Chi Minh City, Vietnam

Antimicrobial-resistant pathogenic members of the Enterobacteriaceae are a well-defined global problem. We hypothesized that one of the main reservoirs of dissemination of antimicrobial resistance genes in Vietnam is non-pathogenic intestinal flora, and sought to isolate antimicrobial-resistant organisms from hospitalized patients and non-hospitalized healthy individuals in Ho Chi Minh City. The results identified substantial faecal carriage of gentamicin-, ceftazidime- and nalidixic acid-resistant members of the Enterobacteriaceae in both hospitalized patients and non-hospitalized healthy individuals. A high prevalence of quinolone resistance determinants was identified, particularly the qnrS gene, in both community- and hospital-associated strains. Furthermore, the results demonstrated that a combination of quinolone resistance determinants can confer resistance to nalidixic acid and ciprofloxacin, even in the apparent absence of additional chromosomal resistance mutations in wild-type strains and laboratory strains with transferred plasmids. These data suggest that intestinal commensal organisms are a significant reservoir for the dissemination of plasmid-mediated quinolone resistance in Ho Chi Minh City.

Role of quinine in the high mortality of intramuscular injection tetanus

There has been considerable uncertainty about the risks and severity of tetanus after intramuscular quinine, a widely used treatment of severe malaria in the rural tropics. We have compared the clinical features and outcome of tetanus in which injection was the only apparent site of infection with tetanus acquired by other routes in patients admitted to the Centre for Tropical Diseases, Ho Chi Minh City, Vietnam. In 1081 consecutive patients with tetanus treated between Jan 26, 1989, and May 27, 1991, 27 followed intramuscular quinine and 15 followed injections of other drugs. Overall mortality was 26% (285/1081). Mortality in patients who had not had preceding injections was 24% (250/1039) compared with 96% (26/27) in the quinine group (relative risk 4.0, 95% CI 3.5-4.6) (p < 0.0001), and 60% (9/15) in the other injections group (2.5, 1.6-3.8) (p < 0.005). 21 patients (78%) in the quinine group died within 72 h of admission compared with 5 (33%) in the other intramuscular injections group (p < 0.01) and 4 (7%) of 54 matched controls (p < 0.0001). Tetanus that follows intramuscular injections has a poor prognosis, but when it follows intramuscular quinine it is usually rapidly fatal.

Emergence of carbapenem-resistant Acinetobacter baumannii as the major cause of ventilator- associated pneumonia in intensive care unit patients at an infectious disease hospital in southern Vietnam

Ventilator-associated pneumonia (VAP) is a serious healthcare-associated infection that affects up to 30 % of intubated and mechanically ventilated patients in intensive care units (ICUs) worldwide. The bacterial aetiology and corresponding antimicrobial susceptibility of VAP is highly variable, and can differ between countries, national provinces and even between different wards in the same hospital. We aimed to understand and document changes in the causative agents of VAP and their antimicrobial susceptibility profiles retrospectively over an 11 year period in a major infectious disease hospital in southern Vietnam. Our analysis outlined a significant shift from Pseudomonas aeruginosa to Acinetobacter spp. as the most prevalent bacteria isolated from quantitative tracheal aspirates in patients with VAP in this setting. Antimicrobial resistance was common across all bacterial species and we found a marked proportional annual increase in carbapenem-resistant Acinetobacter spp. over a 3 year period from 2008 (annual trend; odds ratio 1.656, P = 0.010). We further investigated the possible emergence of a carbapenem-resistant Acinetobacter baumannii clone by multiple-locus variable number tandem repeat analysis, finding a blaOXA-23-positive strain that was associated with an upsurge in the isolation of this pathogen. We additionally identified a single blaNDM-1-positive A. baumannii isolate. This work highlights the emergence of a carbapenem-resistant clone of A. baumannii and a worrying trend of antimicrobial resistance in the ICU of the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.

Effect of magnesium sulphate on urinary catecholamine excretion in severe tetanus.

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Semi-recumbent body position fails to prevent healthcare-associated pneumonia in Vietnamese patients with severe tetanus.

Healthcare-associated pneumonia (HCAP) is a common complication in patients with severe tetanus. Nursing tetanus patients in a semi-recumbent body position could reduce the incidence of HCAP. In a randomised controlled trial we compared the occurrence of HCAP in patients with severe tetanus nursed in a semi-recumbent (30°) or supine position. A total of 229 adults and children (aged ≥1 year) with severe tetanus admitted to hospital in Vietnam, were randomly assigned to a supine (n = 112) or semi-recumbent (n = 117) position. For patients maintaining their assigned positions and in hospital for > 48 h there was no significant difference between the two groups in the frequency of clinically suspected pneumonia [22/106 (20.8%) vs 26/104 (25.0%); p = 0.464], pneumonia rate/1000 intensive care unit days (13.9 vs 14.6; p = 0.48) and pneumonia rate/1000 ventilated days (39.2 vs 38.1; p = 0.72). Mortality in the supine patients was 11/112 (9.8%) compared with 17/117 (14.5%) in the semi-recumbent patients (p = 0.277). The overall complication rate [57/112 (50.9%) vs 76/117 (65.0%); p = 0.03] and need for tracheostomy [51/112 (45.5%) vs 69/117 (58.9%); p = 0.04) was greater in semi-recumbent patients. Semi-recumbent body positioning did not prevent the occurrence of HCAP in severe tetanus patients. [Clinical Trials.gov Identifier: NCT01331252]

In vitro activity of colistin in antimicrobial combination against carbapenem-resistant Acinetobacter baumannii isolated from patients with ventilator-associated pneumonia in Vietnam

Acinetobacter baumannii has become one of the major infection threats in intensive care units (ICUs) globally. Since 2008, A. baumannii has been the leading cause of ventilator-associated pneumonia (VAP) in our ICU at an infectious disease hospital in southern Vietnam. The emergence of this pathogen in our setting is consistent with the persistence of a specific clone exhibiting resistance to carbapenems. Antimicrobial combinations may be a strategy to treat infections caused by these carbapenem-resistant A. baumannii. Therefore, we assessed potential antimicrobial combinations against local carbapenem-resistant A. baumannii by measuring in vitro interactions of colistin with four antimicrobials that are locally certified for treating VAP. We first performed antimicrobial susceptibility testing and multilocus variable number tandem repeat analysis (MLVA) genotyping on 74 A. baumannii isolated from quantitative tracheal aspirates from patients with VAP over an 18-month period. These 74 isolates could be subdivided into 21 main clusters by MLVA and >80 % were resistant to carbapenems. We selected 56 representative isolates for in vitro combination synergy testing. Synergy was observed in four (7 %), seven (13 %), 20 (36 %) and 38 (68 %) isolates with combinations of colistin with ceftazidime, ceftriaxone, imipenem and meropenem, respectively. Notably, more carbapenem-resistant A. baumannii isolates (36/43; 84 %) exhibited synergistic activity with a combination of colistin and meropenem than carbapenem-susceptible A. baumannii isolates (2/13; 15 %) (P = 0.023; Fishers exact test). Our findings suggest that combinations of colistin and meropenem should be considered when treating carbapenem-resistant A. baumannii infections in Vietnam, and we advocate clinical trials investigating combination therapy for VAP.

Prognosis of neonatal tetanus in the modern management era: an observational study in 107 Vietnamese infants

Highlights • Large contemporary case-series in a setting of improved critical care facilities.• Analysis of variables, some not analysed in previous studies/meta-analyses.• Age and weight were associated with a poor outcome.• Delay in admission to hospital and leukocytosis were also associated with a poor outcome.

Neonatal Tetanus in Vietnam: Comprehensive Intensive Care Support Improves Mortality

We report a 66% reduction in neonatal tetanus mortality after introducing a new management bundle integrating antibiotic therapy, muscle relaxation and invasive monitoring. The latter allowed rapid detection of autonomic instability which was treated with magnesium sulphate. This is the first report of its use in neonatal tetanus.

Intrathecal Immunoglobulin for treatment of adult patients with tetanus: A randomized controlled 2x2 factorial trial

Despite long-standing availability of an effective vaccine, tetanus remains a significant problem in many countries. Outcome depends on access to mechanical ventilation and intensive care facilities and in settings where these are limited, mortality remains high. Administration of tetanus antitoxin by the intramuscular route is recommended treatment for tetanus, but as the tetanus toxin acts within the central nervous system, it has been suggested that intrathecal administration of antitoxin may be beneficial. Previous studies have indicated benefit, but with the exception of one small trial no blinded studies have been performed. The objective of this study is to establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus. Secondary objectives: to determine whether the addition of intrathecal tetanus antitoxin reduces autonomic nervous system dysfunction and length of hospital/ intensive care unit stay; whether the addition of intrathecal tetanus antitoxin in the treatment of tetanus is safe and cost-effective; to provide data to inform recommendation of human rather than equine antitoxin. This study will enroll adult patients (≥16 years old) with tetanus admitted to the Hospital for Tropical Diseases, Ho Chi Minh City. The study is a 2x2 factorial blinded randomized controlled trial. Eligible patients will be randomized in a 1:1:1:1 manner to the four treatment arms (intrathecal treatment and human intramuscular treatment, intrathecal treatment and equine intramuscular treatment, sham procedure and human intramuscular treatment, sham procedure and equine intramuscular treatment). Primary outcome measure will be requirement for mechanical ventilation. Secondary outcome measures: duration of hospital/ intensive care unit stay, duration of mechanical ventilation, in-hospital and 240-day mortality and disability, new antibiotic prescription, incidence of ventilator associated pneumonia and autonomic nervous system dysfunction, total dose of benzodiazepines and pipecuronium, and incidence of adverse events. Trial registration: ClinicalTrials.gov NCT02999815 Registration date: 21 December 2016.