Perioperative management and molecular patterns in patients with obstructive sleep apnea

Obstructive sleep apnea (OSA) is a common disorder, both in the general and surgical population. While there is a steadily increased awareness of the disorder both in the society as a whole and within health care, unfortunately, most individuals with OSA still go undiagnosed. The repeated upper airway obstructions causing hypoxias, microarousals and increased sympathetic activation do not only contribute to the classical symptoms of excessive daytime tiredness and nightly snoring but also to increased cardiovascular and metabolic comorbidity. Patients with OSA are found to have an increased risk for perioperative pulmonary and cardiovascular complications, but also increased risk for intensive unit care and prolonged hospital stay after surgery. The aim of this thesis was to investigate the effect of partial neuromuscular blockade on the hypoxic ventilatory regulation in patients with OSA, to evaluate the STOP-Bang questionnaire in a sleep clinic population and to explore whole blood transcriptome and circulating inflammatory biomarkers in patients with OSA compared to matched controls and after three and twelve months of continuous positive airway pressure (CPAP) treatment.

It has previously been shown that the hypoxic ventilatory response (HVR) is reduced by a third during partial neuromuscular blockade in healthy volunteers and that sleep apnea patients have an increased HVR compared to healthy controls. We found that the HVR is reduced by 36% in untreated sleep apnea patients at a train-of-four ratio of 0.7, whilst the hypercapnic ventilatory response was unaffected.

The STOP-Bang questionnaire is designed as a simple screening tool to identify OSA in the surgical population. It consists of eight dichotomous (yes/no) questions, each yes giving one score. In the sleep clinic population, we found that the optimal cut-off for identifying OSA is a score of 5 and to identify at least moderate OSA is a score of 6. In addition, we also showed that a score of ³6 has a sensitivity of 91% to detect moderate-to-severe OSA and that a score <2 can exclude moderate-to-severe OSA by 95%. There was a good correlation between the apnea-hypopnea index and the oxygen desaturation index.

Obstructive sleep apnea is considered a chronic low-grade inflammatory disease and together with increased sympathetic activation and oxidative stress may cause many of the associated comorbidities. To better understand the pathophysiology of the disease, there has been an intense search for biomarkers. We showed that untreated patients with OSA have a downregulation of immune-related genes, including light and heavy chain immunoglobulins and interferon-inducible genes compared to matched controls. However, after three months of CPAP treatment, the gene expression resembled that of the matched controls and finally, after twelve months of treatment, the gene expression returned to the initial untreated state. When exploring circulating inflammatory biomarkers we found that capase 8 and glia cell-line derived neurotrophic factor were downregulated and that monocyte chemoattractant protein 1, fibroblast growth factor 21, neutrophils and neutrophil-to-lymphocyte ratio was upregulated by 3 and/or 12 months CPAP treatment. No inflammatory biomarker was changed in untreated patients with OSA compared to matched controls. However, interleukin 1 alpha, c-reactive protein and erythrocyte sedimentation rate were increased in untreated sleep apnea patients compared to normal body mass index controls.

In conclusion, untreated patients with OSA are as vulnerable to acute hypoxia during partial neuromuscular block as healthy volunteers with a reduced HVR by one-third. They are not protected by their typically increased HVR. The STOP-Bang questionnaire can be an effective screening tool in the sleep population, where nearly all patients with a score of ³6 have at least moderate OSA and a score <2 almost excludes at least moderate OSA. For intermediate scoring (2-5) nightly pulse oximetry can add extra information. There is a difference in the genetic and protein molecular pattern in patients with OSA before and after CPAP treatment in the sense that changes in the transcriptome were found in the untreated state compared to matched controls but not in circulating inflammatory biomarkers. Howevere there was a normalisation of the genetic expression after three months of treatment and a return to the untreated state after twelve months whereas the changes of inflammatory biomarkers mainly appeared after 12 months of CPAP treatment.

List of scientific papers

I. Hypoxic ventilatory response after rocuronium-induced partial neuromuscular blockade in men with obstructive sleep apnoea. Eva Christensson, Anette Ebberyd, Anna Hårdemark Cedborg, Åse Lodenius, Åsa Österlund Modalen, Karl A Franklin, Lars I Eriksson, Malin Jonsson Fagerlund. Anaesthesia. 2020;75(3):338-347.
https://doi.org/10.1111/anae.14806

II. Can STOP-Bang and pulse oximetry dectect and exclude obstructive sleep apnea? Eva Christensson, Karl A Franklin, Carin Sahlin, Andreas Palm, Jan Ulfberg, Lars I Eriksson, Eva Lindberg, Eva Hagel, Malin Jonsson Fagerlund. Anestesia and Analgesia. 2018, 127(3):736-743.
https://doi.org/10.1213/ANE.0000000000003607

III. Whole blood gene expression signature in patients with obstructive sleep apnea and effect of continuous positive airway pressure treatment. Eva Christensson*, Souren Mkrtchian*, Anette Ebberyd, Åsa Österlund Modalen, Karl A Franklin, Lars I Eriksson, Malin Jonsson Fagerlund. Respiratory Physiology and Neurobiology. 2021;294:103746. *These authors contributed equally to the paper.
https://doi.org/10.1016/j.resp.2021.103746

IV. Effect of CPAP treatment on inflammatory biomarkers in patients with obstructive sleep apnea. Eva Christensson, Souren Mkrtchian, Anette Ebberyd, Karl A Franklin, Lars I Eriksson, Malin Jonsson Fagerlund. [Manuscript]