Approach to the Control of Antimicrobial Resistance: Are We Missing the Plot?

How to cite this article: Peter JV. Approach to the Control of Antimicrobial Resistance: Are We Missing the Plot? Indian J Crit Care Med 2020;24(10):899-900.

Tropical Fevers in Indian Intensive Care Units: A Prospective Multicenter Study.

BACKGROUND AND AIMS: Infections in tropics often present as undifferentiated fevers with organ failures. We conducted this nationwide study to identify the prevalence, profile, resource utilization, and outcome of tropical fevers in Indian Intensive Care Units (ICUs). MATERIALS AND METHODS: This was a multicenter prospective observational study done in 34 ICUs across India (July 2013-September 2014). Critically ill adults and children with nonlocalizing fever >48 h and onset < 14 days with any of the following: thrombocytopenia/rash, respiratory distress, renal failure, encephalopathy, jaundice, or multiorgan failure were enrolled consecutively. RESULTS: Of 456 cases enrolled, 173 were children <12 years. More than half of the participants (58.7%) presented in postmonsoon months (August-October). Thrombocytopenia/rash was the most common presentation (60%) followed by respiratory distress (46%), encephalopathy (28.5%), renal failure (23.5%), jaundice (20%), and multiorgan failure (19%). An etiology could be established in 365 (80.5%) cases. Dengue (n = 105.23%) was the most common followed by scrub typhus (n = 83.18%), encephalitis/meningitis (n = 44.9.6%), malaria (n = 37.8%), and bacterial sepsis (n = 32.7%). Nearly, half (35% invasive; 12% noninvasive) received mechanical ventilation, a quarter (23.4%) required vasoactive therapy in first 24 h and 9% received renal replacement therapy. Median (interquartile range) ICU and hospital length of stay were 4 (3-7) and 7 (5-11.3) days. At 28 days, 76.2% survived without disability, 4.4% had some disability, and 18.4% died. Mortality was higher (27% vs. 15%) in patients with undiagnosed etiology (P < 0.01). On multivariate analysis, multiorgan dysfunction syndrome at admission (odds ratio [95% confidence interval]-2.8 [1.8-6.6]), day 1 Sequential Organ Failure Assessment score (1.2 [1.0-1.3]), and the need for invasive ventilation (8.3 [3.4-20]) were the only independent predictors of unfavorable outcome. CONCLUSIONS: Dengue, scrub typhus, encephalitis, and malaria are the major tropical fevers in Indian ICUs. The data support a syndromic approach, point of care tests, and empiric antimicrobial therapy recommended by Indian Society of Critical Care Medicine in 2014.

Tropical fevers: Management guidelines.

Tropical fevers were defined as infections that are prevalent in, or are unique to tropical and subtropical regions. Some of these occur throughout the year and some especially in rainy and post-rainy season. Concerned about high prevalence and morbidity and mortality caused by these infections, and overlapping clinical presentations, difficulties in arriving at specific diagnoses and need for early empiric treatment, Indian Society of Critical Care Medicine (ISCCM) constituted an expert committee to develop a consensus statement and guidelines for management of these diseases in the emergency and critical care. The committee decided to focus on most common infections on the basis of available epidemiologic data from India and overall experience of the group. These included dengue hemorrhagic fever, rickettsial infections/scrub typhus, malaria (usually falciparum), typhoid, and leptospira bacterial sepsis and common viral infections like influenza. The committee recommends a 'syndromic approach' to diagnosis and treatment of critical tropical infections and has identified five major clinical syndromes: undifferentiated fever, fever with rash / thrombocytopenia, fever with acute respiratory distress syndrome (ARDS), fever with encephalopathy and fever with multi organ dysfunction syndrome. Evidence based algorithms are presented to guide critical care specialists to choose reliable rapid diagnostic modalities and early empiric therapy based on clinical syndromes.

Dominance of international high-risk clones in carbapenemase-producing Pseudomonas aeruginosa: Multicentric molecular epidemiology report from India.

BACKGROUND: Pseudomonas aeruginosa is one of the most common opportunistic pathogens that cause severe infections in humans. The burden of carbapenem resistance is particularly high and is on the rise. Very little information is available on the molecular mechanisms and its clonal types of carbapenem-resistant P. aeruginosa seen in Indian hospitals. This study was undertaken to monitor the ß-lactamase profile and to investigate the genetic relatedness of the carbapenemase-producing (CP) P. aeruginosa collected across different hospitals from India. MATERIALS AND METHODS: A total of 507 non-duplicate, carbapenem-resistant P. aeruginosa isolated from various clinical specimens collected during 2014-2017 across seven Indian hospitals were included. Conventional multiplex polymerase chain reaction for the genes encoding beta-lactamases such as extended-spectrum beta-lactamase (ESBL) and carbapenemase were screened. A subset of isolates (n = 133) of CP P. aeruginosa were genotyped by multilocus sequence typing (MLST) scheme. RESULTS: Of the total 507 isolates, 15%, 40% and 20% were positive for genes encoding ESBLs, carbapenemases and ESBLs + carbapenemases, respectively, whilst 25% were negative for the ß-lactamases screened. Amongst the ESBL genes, blaVEB is the most predominant, followed by blaPER and blaTEM, whilst blaVIM and blaNDM were the most predominant carbapenemases seen. However, regional differences were noted in the ß-lactamases profile across the study sites. Genotyping by MLST revealed 54 different sequence types (STs). The most common are ST357, ST235, ST233 and ST244. Six clonal complexes were found (CC357, CC235, CC244, CC1047, CC664 and CC308). About 24% of total STs are of novel types and these were found to emerge from the high-risk clones. CONCLUSION: This is the first large study from India to report the baseline data on the molecular resistance mechanisms and its association with genetic relatedness of CP P. aeruginosa circulating in Indian hospitals. blaVIM- and blaNDM-producing P. aeruginosa is the most prevalent carbapenemase seen in India. Majority of the isolates belongs to the high-risk international clones ST235, ST357 and ST664 which is a concern.

Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype).

We earlier found an association between anorexia nervosa (AN) restrictive subtype (AN-R) and an inserted sequence within the NETpPR, a polymorphic region located in the promoter of the solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 (SLC6A2) gene. To further examine the noradrenergic system in AN-R we performed an association study with a functional polymorphism (MAOA-uVNTR) in the promoter of the monoamine oxidase A (MAOA) gene. Since monoamine oxidase A metabolises noradrenalin, a positive association with the MAOA gene would be biologically plausible. The transmission disequilibrium test and 95 trios/duos (AN-R females+biological parents) showed the main effect of the longer, more transcriptionally active form of the MAOA-uVNTR (MAOA-L) to be statistically non-significant (McNemar's chi(2)=1.4, df=1, P=0.238, odds ratio: 1.4, 95% CI 0.8-2.7). A case-control approach supported this finding. We then stratified the MAOA-uVNTR TDT data according to the (a) NETpPR genotype of the AN-R females, and (b) NETpPR allele transmitted from NETpPR-S4/L4 heterozygous mothers. In both cases, contingency table analysis revealed previously unreported gene-gene interaction between the MAOA and SLC6A2 genes (P=0.019 and 0.019, respectively). Receiving an MAOA-L allele more than doubles the risk for developing AN-R, conditional on an individual also being a NETpPR-L4 homozygote (stratum-specific odds ratio: 2.4, 95% CI 1.1-6.0). These results suggest important involvement of the noradrenergic system in the biological underpinnings of AN-R.

The effect of zileuton on antipyrine and indocyanine green disposition.

The effects of single and multiple oral doses of zileuton on the pharmacokinetics of antipyrine and indocyanine green were studied in 16 healthy, nonsmoking adult men by means of a double-blind, randomized, parallel placebo-controlled design. Indocyanine green disposition was not significantly altered by zileuton. Plasma antipyrine clearance declined by 20% (p < 0.0005) and 52% (p < 0.0005) after single and multiple dose zileuton exposure, respectively. Total urinary recovery of unchanged antipyrine and metabolites decreased with zileuton exposure. Selective declines from baseline of 16% (p = 0.007) and 20% (p = 0.003) after single-dose zileuton and 30% (p < 0.0005) and 43% (p < 0.0005) after multiple-dose zileuton were detected in recovery of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine, respectively. Urinary recovery of the N-demethylantipyrine metabolite norantipyrine and percent of conjugation of 3-hydroxymethylantipyrine were unchanged by zileuton. In conclusion, zileuton therapy has no detectable effect on indocyanine green disposition but exerts marked effects on antipyrine plasma and urine metabolite disposition.

Quantifying hepatic function in the presence of liver disease with phenazone (antipyrine) and its metabolites.

The disposition of phenazone (antipyrine), a low extraction compound with low protein binding, is known to be altered in the presence of various types of hepatic dysfunction. As such, its pharmacokinetics may be useful in the objective characterisation of altered liver function. Understanding the known effects of various liver disease states upon the disposition of this probe may provide insight into future applications. This article provides a review of background information about normal plasma phenazone pharmacokinetics, urinary metabolite disposition and tabulations of reported total body clearances of the drug in the presence of cirrhosis, fatty liver, hepatitis and cholestasis in humans. An estimate is made of the sensitivity and specificity of phenazone testing for the verification of the presence of cirrhosis based on this compiled literature.

Redistribution and enhanced urinary excretion of 2,2',4,4',5,5'-hexachlorobiphenyl (HCB) in rats using HCB-specific IgG and Fab fragments.

Drug-specific antibody fragments can enhance the elimination of some drugs by redistributing drug from tissues into serum and allowing renal excretion of the drug-antibody complex. This approach could potentially be used to enhance the elimination of compounds such as polychlorinated biphenyls that have very long elimination half-lives. As a first step in testing this hypothesis, the effects of 2,2',4,4',5,5'-hexachlorobiphenyl (HCB)-specific antibodies and their corresponding Fab fragments on HCB disposition were studied in rats. Antibodies to HCB were produced in chickens, and the corresponding Fab fragments were produced by digestion with papain. To study antibody effects on HCB distribution, [14C]HCB (0.1 mg) was administered i.v. to rats. Two weeks later, after distribution to tissues was complete, anti-HCB IgG or control IgG was administered i.v. The serum radiolabel concentration 2 hr after IgG administration increased 185 +/- 64% in animals treated with specific antibody vs 51 +/- 19% in control animals (P < 0.001). The increase in serum radiolabel concentration was apparent within 30 min and maximal at 2 hr. To study effects on HCB excretion, anti-HCB or control Fab fragment was administered 2 weeks after [14C]HCB. Urinary HCB excretion over the next 24 hr, measured by gas chromatography, was 10-fold greater in the group treated with anti-HCB Fab (P < 0.01). These data demonstrate that anti-HCB IgG can redistribute HCB rapidly from tissues into serum and that anti-HCB Fab can enhance urinary HCB excretion. While the magnitude of these changes was small, the data suggest that increasing HCB excretion using drug-specific antibody fragments is feasible, and can serve as a model for enhancing the excretion of compounds that have very long elimination half-lives.

Is the aggressive management of hyperlipidemia in nephrotic syndrome mandatory?

The development of the nephrotic syndrome is associated with a lipid profile characterized by increased total and low density lipoprotein cholesterol. Although total high density lipoprotein (HDL) values may be in the normal range, there is frequently abnormalities of HDL subclasses, with reduction of the mature HDL2 subfraction. While these lipid changes may be considered a risk for atherosclerosis, they revert to normal with remission of the nephrotic syndrome. However, with chronic nephrotic range proteinuria, these abnormalities persist and may also be associated with increased levels of lipoprotein (a), increased levels of very light density lipoprotein and further reductions in HDL. These factors could all contribute to greater risk for atherosclerosis. Although coronary artery disease is frequently seen in patients with end-stage renal disease, and many uncontrolled studies in patients with chronic nephrotic syndrome have suggested an increased prevalence of cardiovascular disease, no prospective studies to evaluate relationship between lipid abnormalities and cardiac disease have been performed in patients with the nephrotic syndrome. Recent experimental data have also suggested a relationship between hyperlipidemia and progressive renal injury. Unfortunately, human epidemiological data are incomplete in correlating lipid changes with renal disease in patients with chronic nephrotic syndrome. No therapeutic trials have tested whether or not pharmacologic interventions will benefit either the cardiac or renal disease that ensues in patients with chronic persistent nephrotic syndrome. Thus, considerably more data are needed to help clarify this important area.

Pharmacokinetics of pilocarpine in subjects with varying degrees of renal function.

Data from three separate single-center studies were combined to assess the pharmacokinetics of orally administered pilocarpine. Pilocarpine concentration-time data were used to generate a data set including 42 subjects (34 males, 8 females) with varying degrees of renal function (average of two estimated creatinine clearance rates of 10 to 112 mL/min). Age ranged from 19 to 88 years. Subjects received single oral doses (range: 2.5-20 mg) of pilocarpine. Plasma samples were collected at time 0; at 20 and 40 minutes; and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours following dose administration. Cmax and AUC were normalized to a 5 mg exposure in those subjects who received doses other than 5 mg. Plasma pilocarpine concentrations were determined by gas chromatography/mass spectrometry. The pharmacokinetic parameters (elimination rate constant, Cmax, tmax, AUC, Vd/F, and Cl/F) in subjects with impaired renal function were similar to results found in other pharmacokinetic studies involving normal healthy volunteers with only Cmax being significantly higher (p < 0.05). No significant regression relationships were noted between creatinine clearance and pilocarpine elimination rate constant, tmax, Vd/F, Cl/F, or AUC. Pilocarpine clearance does not appear to be impaired in patients with varying degrees of renal insufficiency.

Factors associated with the risk of liver enzyme elevation in patients with type 2 diabetes treated with a thiazolidinedione.

STUDY OBJECTIVE: To characterize frequency of liver enzyme elevation in patients with type 2 diabetes mellitus receiving troglitazone. DESIGN: Retrospective study. SETTING: Hospital-affiliated medical center. PATIENTS: Two hundred ninety-one patients with type 2 diabetes mellitus. INTERVENTION: Data from patients with an average troglitazone exposure of 412.7 +/- 255.6 days were studied. MEASUREMENTS AND MAIN RESULTS: Enzyme elevations more than 1.5 times the upper limit of normal (ULN) occurred in 17 patients (5.8%) and more than 3-fold elevations in 6 (2.1%). The relationship among enzyme elevation events, demographic factors, duration of troglitazone exposure, frequency of monitoring, and concurrent drugs (limited to glucose and lipid-lowering agents) was assessed by multiple logistic regression. Age was an independent predictor of risk (p=0.009), and concurrent insulin therapy approached statistical significance (p=0.051) for 1.5-fold ULN elevation in liver enzymes. Age and concurrent therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were the only significant predictors of 3-fold ULN elevations (p=0.03 and p=0.04, respectively). CONCLUSION: Several factors appear to increase the risk of enzyme elevation events in patients treated with troglitazone.

Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects.

STUDY OBJECTIVE: To evaluate and compare the relationship between dosage and coagulation parameters, as well as safety profiles, of ascending bolus and infusion dosages of argatroban versus heparin in three phase I studies. DESIGN: Two randomized, double-blind studies compared argatroban and heparin, and one open-label, dose-escalation study further evaluated argatroban. SETTING: University teaching hospital clinical research unit. PATIENTS: Healthy men (aged 22-62 yrs). INTERVENTION: In the first study, 36 subjects received an argatroban 30-, 60-, 120-, or 240-microg/kg bolus, or a heparin 30-, 60-, 120-, or 240-U/kg bolus for three subjects, then amended to 15, 30, 60, or 120 U/kg. In the second study, 37 subjects received argatroban 1.25, 2.5, 5, or 10 microg/kg/minute with or without a 250-microg/kg bolus, or heparin 0.15, 0.20, 0.25, or 0.30 U/kg/minute with or without a 125-U/kg bolus. In the third study (open-label), nine subjects received an argatroban 250-microg/kg bolus plus an infusion of 15, 20, 30, and 40 microg/kg/minute. MEASUREMENTS AND MAIN RESULTS: When administered as a bolus dose in the first study, argatroban and heparin both produced dose-related increases in activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. Dissipation of anticoagulant effect was approximately 4-fold faster for argatroban than for heparin. When administered by infusion with or without a bolus in the second study, argatroban, but not heparin, produced predictable dose-related increases in ACT and aPTT that were generally consistent across both effect measures and modes of administration. Effect steady state was attained by five or more subjects per dosing group receiving argatroban (5-9) but typically two or fewer subjects per group receiving heparin (0-7). Furthermore, upon cessation of infusion, anticoagulant effects dissipated faster for argatroban (effect half-life 18-41 min) than for heparin (effect half-life 23-134 min). When argatroban was infused without a bolus, peak and effect steady-state values for ACT and aPTT generally were attained within 1-3 hours. Data from the second and third studies show that for argatroban dosages up to 40 microg/kg/minute, plasma drug concentrations attained at 4 hours of infusion increased linearly with dose, and weight-adjusted plasma clearance was dose independent. In all studies, argatroban and heparin were well tolerated. CONCLUSION: Anticoagulation was more predictable with argatroban than with heparin as measured by ACT and aPTT, with comparable safety profiles.

Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers.

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmacokinetics and 6 beta-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5 mg of doxylamine succinate, placebo, or 30 mg of phenobarbital administered orally every 6 h for 17 days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45 mL/h/kg) and nonrenal (35 versus 44 mL/h/kg) clearances and 6 beta-hydroxycortisol excretion (338 versus 529 micrograms) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.

Accuracy of technicians versus pharmacists in checking syringes prepared for a dialysis program.

The accuracy of pharmacy technicians versus pharmacists in checking drug doses prepared in syringes for a dialysis program was studied. Three pharmacy technicians from the pharmacy of a regional kidney disease program in Minnesota participated in the study after completing a training program and after common preparation errors had been identified by pharmacists. From November 1995 to April 1996, the technicians used labels printed from a database of pharmacist-verified orders to prepare and label i.v. syringes. Four medications were used-epoetin alfa, calcitriol, heparin prepared from beef lung, and heparin prepared from porcine intestinal mucosa. Each syringe was checked by one of nine pharmacists for accuracy of dose and medication, and all errors were recorded. The technicians checked syringes prepared by other technicians and also recorded errors. Accuracy rates (percentages of syringes correctly evaluated) for pharmacists and technicians were compared. A total of 10,608 syringes were checked. Accuracy rates for pharmacists and pharmacy technicians were 99.86% and 99.83%, respectively. Accuracy rates in checking syringes did not differ significantly between pharmacists and technicians in this study setting.

Prevalence & pathogenesis of hypophosphatemia in ventilated patients.

Hypophosphatemia was found in 12 (43%) patients within 24-36 h of mechanical ventilation in a group of 28 patients in an intensive care unit. The hypophosphatemic patients had a significant lowering of renal phosphorus threshold (P = 0.005) and inappropriate phosphaturia. These abnormalities resolved once ventilation was discontinued. Serum parathyroid hormone (PTH) levels were unaltered in this group of patients suggesting that some factor other than PTH was responsible for hypophosphatemia. This study has demonstrated that abnormalities of renal phosphate handling can cause hypophosphatemia in ventilated patients.

Comparison of disease-specific and a generic quality of life measure in patients with bronchial asthma.

BACKGROUND: Quality of life is being increasingly recognized as an important outcome in chronic and terminal illnesses. There are few publications from India on the characteristics of the instrument that measures quality of life in clinical trials. We describe a method for choosing an appropriate instrument in a randomized trial. METHODS: We selected thirty-two patients with bronchial asthma randomly and evaluated them to compare the validity and responsiveness of the disease-specific quality of life instrument in asthma (AQL) and the generic quality of life instrument, 'Sickness impact profile' (SIP), to detect changes in their health status. Validity was determined by a priori constructs (construct validation) and the responsive coefficient was calculated by determining the relationship to the 'minimal significant change in asthma score' and the 'variability' seen in this change in stable patients. RESULTS: The constructs used in validating the scores were that the change in quality of life score would correlate (i) highly with change in self-assessment of the disease (r > 0.7), (ii) moderately with change in physician assessment of the disease (r > 0.5), and (iii) minimally with change in peak flow reading (r > 0.3). We found both instruments to have good construct validity. The responsiveness coefficients noted for AQL and SIP were 1.8 (CI 0.65-3) and 0.7 (CI 0.3-1.2), respectively. CONCLUSIONS: Though both AQL and SIP were valid measures of quality of life, AQL is likely to be more capable of detecting smaller changes in the health status of patients with bronchial asthma and hence was chosen as the instrument in the proposed clinical trial.

Cost-effectiveness of inhaled beta-agonists v. oral salbutamol in asthma: a randomized double-blind cross-over study.

BACKGROUND: Oral beta-stimulants are widely used in the management of chronic asthma in India, in spite of evidence suggesting the superiority of inhaled medication in achieving maximum bronchodilatation. An economic evaluation was performed in a randomized double-blind cross-over trial to evaluate the role of adjuvant oral beta-stimulants in the treatment of asthma. METHODS: Patients who had seasonal or perennial asthma and were using metered dose inhalers for control of symptoms were randomly selected for the study. They received either 4 mg of oral salbutamol or placebo as adjuvant treatment. During the study they controlled their symptoms by adjusting the dose of the inhaler medication. A cost minimization technique was used to assess the economic impact of this intervention in the treatment and control periods. A sensitivity analysis was performed to assess the robustness of the conclusions. RESULTS: The mean cost was significantly greater in the treatment period and a patient lost approximately Rs 20 per month (CI: 13 to 27; p = 0.001) as a result of the adjuvant treatment. There was no significant difference in the quality of life or peak expiratory flow rate during the two periods. The patients also noted mild but significantly increased tremors (p = 0.01) and palpitations (p = 0.001) during the treatment period. There was no treatment-to-period interaction. CONCLUSION: Adjuvant oral beta-agonists do not improve the quality of life or bronchodilatation in asthmatics using an inhaled beta-agonist for control of symptoms.

Drug interaction: rifampicin and glibenclamide.

BACKGROUND: Rifampicin is a potent inducer of the hepatic microsomal enzyme system. However, the drug has been shown to cause clinically important interactions with many drugs. This study was designed to test the interaction of rifampicin with the oral hypoglycaemic agent glibenclamide. METHODS: Twenty-nine well-controlled diabetic patients on a combination therapy of diet and glibenclamide, and willing to participate in the trial, received a daily dose of 450 mg (body weight < 50 kg) or 600 mg (body-weight > 50kg) of rifampicin for 10 days. RESULTS: There was a significant (p < 0.001) worsening of fasting and post-prandial blood sugar after administration of rifampicin. Dose modification of glibenclamide was required in 15 of the 17 patients in whom the diabetes became uncontrolled. Blood sugar normalized by day 6 after stopping rifampicin in all patients. CONCLUSION: Rifampicin and glibenclamide interact. Therefore, necessary dose modifications should be made in order to achieve euglycaemia if these two drugs are given together.

A randomized double-blind sham-controlled study of intrathecal human anti-tetanus immunoglobulin in the management of tetanus.

BACKGROUND: Tetanus is a major cause of mortality and morbidity in developing countries. Various modalities of treatment to prevent progression of the disease and alter its outcome have been tried. This study was designed to evaluate the role of intrathecal human anti-tetanus immunoglobulin (TIG) in the management of tetanus. METHODS: Thirty-six adult patients presenting to an university-affiliated teaching hospital were stratified based on the severity of disease into mild and severe disease, and subsequently randomly allocated to receive either 250 i.u. of TIG intrathecally or a sham procedure mimicking the lumbar puncture. RESULTS: In mild tetanus, TIG administration significantly retarded the rate of progression (p = 0.05), reduced the duration of hospital (p = 0.01) and intensive care unit stay (p = 0.05), need for tracheostomies (p = 0.03) and the dose of sedatives required for control of spasms (p = 0.01). In mild tetanus, the mortality rates were 20% and 30% in the treated and control groups, respectively. CONCLUSION: We suggest that TIG is useful in reducing the morbidity, progression of disease and mortality in patients presenting with mild tetanus.

Hyponatraemia and hiccups.

BACKGROUND: Hiccups are observed in many patients with hypohatraemia. We performed a case-control study to evaluate their association in a referral teaching hospital in South India. METHODS: Fifty consecutive patients who developed hiccups during an 18-month period were studied. They were categorized according to age group and diagnosis and controls matched for age and sex were selected from patients admitted on the same day in the medical wards. Hiccups were graded on a four-point severity scale at recruitment and every day till day 7 or till hiccups subsided. RESULTS: The step-wise logistic regression analysis done to establish independent association showed that for every 10 mEq/L reduction in serum sodium, patients were 17 times (p = 0.001; confidence interval: 4-87) at risk of developing hiccups. The only other significant determinant of the symptom was the diagnostic category of renal failure (odds ratio = 128; confidence interval: 1-1420). The number of patients who had hyponatraemia with varying severity of hiccups showed a dose-response relationship. The crude odds ratios were 7, 58 and 320 for mild, moderate and severe hiccups. CONCLUSION: There is a strong and independent association between hyponatraemia and hiccups in hospitalized patients. A causative association is suggested by the dose-response relationship demonstrated in the study. In many hospitals in developing countries where measurement of serum sodium is difficult and unreliable, it is important to be aware of this association since it can be easily corrected.