Early postoperative orthostatic intolerance: pathophysiology and clinical implications

Early postoperative ambulation is an important component of enhanced recovery after surgery (ERAS) pathways. Early ambulation may avoid the deleterious physiological and psychological effects of bed rest, including atelectasis, pneumonia, deep-vein thrombosis, muscle wasting, and functional decline. Failure to mobilize early may be related to patient characteristics (for example advanced age, sex, BMI, malnutrition, frailty, and cognitive dysfunction), inadequate pain control, opioid-related adverse events (for example nausea and vomiting, dizziness, and oversedation), delirium, and surgical and medical complications. Also, the presence of catheters (for example urinary and epidural catheters) and tubes and drains (for example nasogastric tubes and wound drains) can delay ambulation. Early postoperative orthostatic intolerance is one of the factors that can hinder early ambulation. It occurs despite adequate implementation of optimized ERAS pathways that minimize the impact of potential contributing factors. However, postoperative orthostatic intolerance is frequently under-diagnosed or misdiagnosed, and strategies aiming to reduce its incidence have received little attention. The aim of this article is to provide an overview of the current evidence regarding the pathophysiology of orthostatic intolerance and to discuss possible interventions to prevent and/or treat it. Orthostatic intolerance is characterized by dizziness, blurred vision, light-headedness, nausea and vomiting, palpitations, tremulousness, or syncope after postural changes, such as sitting and standing, regardless of arterial blood pressure (Fig. 1)1,2. Severe orthostatic intolerance may be defined as an inability to mobilize due to unbearable symptoms, with or without a fall in arterial blood pressure. In contrast, orthostatic hypotension is defined as a decrease in systolic arterial pressure ≥20 mmHg or diastolic arterial pressure ≥10 mmHg during sitting or standing when compared with measurements in the supine position2. Common symptoms and signs of orthostatic intolerance Background graphic from https://www.freepik.com. The pathophysiology of postoperative orthostatic intolerance is complex and multifactorial (Fig. 2, top); it includes a dysregulated autonomic nervous system due to increased parasympathetic activity (that is high vagal tone) and reduced sympathetic activity (that is an impaired vasopressor response—an impaired increase in noradrenaline (norepinephrine)) during early postoperative mobilization (that is the transition from the supine posture to standing and walking)3,4. The progression to severe orthostatic intolerance symptoms appears to be primarily due to an inadequate heart rate response, bradycardia, and declining cardiac output5,6. Intravascular volume status and acute mild blood loss may also contribute to orthostatic intolerance despite a preserved heart rate variability and autonomic function during mobilization6. Data suggest that cardiovascular and cerebral tissue oxygenation are reduced in patients with severe orthostatic intolerance. The surgical stress response incorporates neuroendocrine, metabolic, inflammatory, and immune mechanisms, and depends upon the extent and invasiveness of the surgical procedure. Possible pathophysiological mechanisms contributing to postoperative orthostatic intolerance (top) and potential interventions to prevent orthostatic intolerance (bottom) Factors influencing orthostatic intolerance can be categorized as patient-related, anaesthetic and analgesic, and surgical. Anaemia does not appear to influence the incidence of orthostatic intolerance7. Residual effects of anaesthetic drugs may contribute; however, modern techniques that include the use of short-acting anaesthetic agents and neuromuscular blocking drugs, as well as an opioid-sparing approach, might allow rapid recovery and reduce the risk8,9. Opioids can impair orthostatic cardiovascular responses (that is impair sympathetically mediated vasoconstriction during postural changes) and can reduce cerebral perfusion during mobilization. Administration of morphine 0.1 mg/kg has been shown to increase the incidence of orthostatic intolerance after lower extremity arthroplasty10 and continuous postoperative fentanyl infusion has been shown to have the same effect11. Of note, the use of opioid-free anaesthesia using adjuncts such as dexmedetomidine, lidocaine, ketamine, and magnesium may contribute8; however, when compared with spinal anaesthesia, general anaesthesia leads to more favourable recovery characteristics after total hip and knee arthroplasty12,13. Preoperative identification of patients at risk of postoperative orthostatic intolerance may allow the use of appropriate interventions (Fig. 2, bottom), although predicting this risk is challenging. The implementation of ERAS pathways might facilitate early postoperative ambulation14. Because α-adrenoceptor dysfunction can influence postoperative orthostatic intolerance, α-adrenergic agonists may be effective. However, preoperative oral midodrine, an α-adrenergic agonist, did not significantly influence the incidence of orthostatic intolerance during early mobilization after total hip arthroplasty15. The use of general anaesthetic techniques that allow early recovery8, aggressive nausea and vomiting prophylaxis, and opioid-sparing multimodal analgesia regimens8 allow early ambulation. Although intraoperative pre-incision glucocorticoids have been shown to attenuate surgical inflammatory stress responses, they did not reduce the occurrence of orthostatic intolerance16. Intraoperative hypovolaemia and subsequent reduced postoperative intravascular volume can influence postoperative mobilization6. However, optimization of intraoperative intravascular volume using goal-directed fluid administration did not reduce the prevalence of orthostatic intolerance4. Patients with orthostatic intolerance had impaired haemodynamic and noradrenaline responses on mobilization4, suggesting that both adequate cardiac preload and intact regulation of vasomotor tone are necessary to prevent orthostatic intolerance. The lack of awareness of the benefits of early ambulation, the lack of a culture that prioritizes early mobilization after surgery, the lack of resources, and patients’ historical beliefs in limited activity or complete bed rest may contribute to delayed ambulation. In this context, repeated orthostatic challenges have been reported to restore orthostatic tolerance in non-surgical patients with syncope17. Consequently, optimal approaches to postoperative care may include early attempts to mobilize and, if not successful, modifiable factors (for example sedation, inadequate pain control, opioid overdosing, hypovolaemia, etc.) should be addressed. High-quality studies are required to systematically and reliably determine the incidence and risk factors of orthostatic intolerance. Because several elements of ERAS pathways other than postoperative ambulation may influence its occurrence, future studies on orthostatic intolerance should include adequately implemented ERAS pathways. Furthermore, the lack of consistent assessment of ambulation (for example time out of bed, sitting/standing, distance walked, number of steps walked, accelerometry, etc.) and lack of well-defined mobilization protocols, including approaches to ambulation (that is staff-directed or patient-directed), complicate research in this field. The use of novel trial designs (for example enrichment strategies or adaptive enrichment designs) might improve the likelihood of detecting the best interventions for specific patients undergoing a defined surgical procedure. The pathophysiology of orthostatic intolerance is complex and multifactorial, and approaches to prevent and/or treat it remain elusive. Previous studies have reported lack of improvement with optimizing postoperative pain, goal-directed fluid therapy, α1-adrenoreceptor agonists (midodrine), and glucocorticoids. Future studies assessing strategies to reduce postoperative orthostatic intolerance need to consider the complexity of its pathophysiology. Early mobilization is advantageous and awareness of orthostatic intolerance may reduce the possibility of falls and delayed recovery. The authors have no funding to declare. Girish P. Joshi (Conceptualization, Writing—original draft, Writing—review & editing), Dileep N. Lobo (Conceptualization, Writing—review & editing), and Henrik Kehlet (Conceptualization, Writing—review & editing)