Urinary catecholamine excretion, cardiovascular variability, and outcomes in tetanus

Abstract

Severe tetanus is characterized by muscle spasm and cardiovascular system disturbance. The pathophysiology of muscle spasm is relatively well understood and involves inhibition of central inhibitory synapses by tetanus toxin. That of cardiovascular disturbance is less clear, but is believed to relate to disinhibition of the autonomic nervous system. The clinical syndrome of autonomic nervous system dysfunction (ANSD) seen in severe tetanus is characterized principally by changes in heart rate and blood pressure which have been linked to increased circulating catecholamines. Previous studies have described varying relationships between catecholamines and signs of ANSD in tetanus, but are limited by confounders and assays used. In this study, we aimed to perform detailed characterization of the relationship between catecholamines (adrenaline and noradrenaline), cardiovascular parameters (heart rate and blood pressure) and clinical outcomes (ANSD, mechanical ventilation required, and length of intensive care unit stay) in adults with tetanus, as well as examine whether intrathecal antitoxin administration affected subsequent catecholamine excretion. Noradrenaline and adrenaline were measured by ELISA from 24-h urine collections taken on day 5 of hospitalization in 272 patients enrolled in a 2 × 2 factorial-blinded randomized controlled trial in a Vietnamese hospital. Catecholamine results measured from 263 patients were available for analysis. After adjustment for potential confounders (i.e., age, sex, intervention treatment, and medications), there were indications of non-linear relationships between urinary catecholamines and heart rate. Adrenaline and noradrenaline were associated with subsequent development of ANSD, and length of ICU stay.

Keywords: Autonomic nervous system dysfunction; Cardiovascular; Catecholamine; Infectious diseases; Intensive care; Mechanical ventilation; Tetanus.

Fig. 1.

24-h urinary catecholamine excretion (nmol/day) and cardiovascular parameters on the 5th day of treatment. A Maximum systolic blood pressure (SBP), B minimum systolic blood pressure, C maximum heart rate (HR), and D minimum heart rate; mmHg millimeter of mercury, bpm beats per minute. The vertical lines represent the frequency counts of outcome variables. P-values indicate evidence for overall relationships between catecholamines and cardiovascular parameters measured from models via restricted cubic splines. All predictions are shown for age 48 years, male sex, equine intramuscular treatment interventions, and total doses of benzodiazepines of 2300 mg/day