The four-dimensional stress test: Psychological, sympathetic–adrenal–medullary, parasympathetic and hypothalamic–pituitary–adrenal responses following inhalation of 35% CO2

Wetherell, Mark A.; Crown, Anna L.; Lightman, Stafford L.; Miles, Jeremy N.V.; Kaye, Joey; Vedhara, Kavita

doi:10.1016/j.psyneuen.2006.02.005

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Volume 31, Issue 6 , Pages 736-747, July 2006

The four-dimensional stress test: Psychological, sympathetic–adrenal–medullary, parasympathetic and hypothalamic–pituitary–adrenal responses following inhalation of 35% CO₂

Mark A. Wetherell
- MRC Health Services Research Collaboration, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK
- Corresponding author. Address: MRC Health Services Research Collaboration, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK. Tel.: +44 117 928 7228; fax: +44 117 928 7236.
Anna L. Crown
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK
Stafford L. Lightman
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK
Jeremy N.V. Miles
- Department of Health Sciences (Area 42), University of York, York YO10 5DD, UK
Joey Kaye
- Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia
Kavita Vedhara
- MRC Health Services Research Collaboration, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, UK

Received 1 March 2005; received in revised form 15 February 2006; accepted 17 February 2006.

Summary

Background

Hypercapnia is a threat to homeostasis and results in neuroendocrine, autonomic and anxiogenic responses. The inhalation of carbon dioxide (CO₂) may, therefore, provide a good paradigm for exploring the pathways by which stress can lead to increased susceptibility to ill-health through physiological and psychological stress reactivity. The current study was designed, therefore, to assess the psychological and physiological responses to the inhalation of CO₂.

Methods

Healthy participants (N=24) inhaled a single vital capacity breath of a mixture of CO₂ (35%) and oxygen (65%). Blood pressure and heart rate were recorded for 5min before and after the test and blood and saliva samples were taken immediately before and 2, 10, 20 and 30min post-inhalation for the measurement of noradrenaline, salivary and serum cortisol and salivary α amylase. In addition, psychosomatic symptoms were recorded immediately before and after the test. The same protocol was repeated 4–6 weeks later at the same time of day.

Results

A single inhalation of CO₂ increased blood pressure, noradrenaline, salivary α amylase and psychosomatic symptoms, but decreased heart rate at both testing sessions. Analyses of salivary cortisol data revealed that 70% of the sample could be reliably classified as either responders (i.e. demonstrated a post-CO₂ cortisol increase) or non-responders (i.e. responded with a decrease or no change in cortisol following CO₂) at both test sessions. Responders also perceived the test to be more aversive than non-responders.

Conclusions

Inhalation of 35% CO₂ reliably stimulated the key mechanisms involved in the human stress response. The inter-individual differences in the reactivity of the hypothalamic–pituitary–adrenal axis were also related to differences in the perception of the test.

Keywords: Carbon dioxide inhalation, 35% CO₂ stress test, HPA and SAM axes, Stress reactivity, Parasympathetic activation