Orthostatic intolerance after intravenous administration of morphine: incidence, haemodynamics and heart rate variability analysis

Abstract

Enhanced recovery after surgery (ERAS) is a multimodal peri-operative care pathway designed to counteract the pathophysiological effects of surgical stress [1]. Early postoperative mobilisation is a key concept in ERAS protocols, but it may be delayed or prevented by orthostatic intolerance. Postoperative orthostatic intolerance is defined as subjective symptoms of dizziness; nausea; blurred vision; feeling feverish; vomiting; pre-syncope; or syncope upon postural change after surgery [2]. The pathophysiology of postoperative orthostatic intolerance is not yet fully explained, but it appears to be the final common pathway for many peri-operative factors, such as inflammation; hypovolaemia; anaesthesia; pain; and opioid usage [3]. Opioids are ubiquitous in ERAS multimodal analgesic regimes, despite opioid-sparing approaches and numerous well-known side effects [4]. Opioids can potentially contribute to the development of orthostatic intolerance due to their vagotonic, pro-emetic and vestibular effects [5]. We decided to isolate and investigate the effect of morphine from other, potentially contributing, peri-operative factors by performing all measurements before surgery. This prospective observational cohort study was approved by the local ethics committee. We included 26 patients undergoing lower extremity arthroplasty. Patient flow and exclusion criteria are shown in online Supporting Information Figure S1. A pre-operative standardised mobilisation procedure consisting of supine rest (5 min), sitting (3 min), standing (3 min) and supine rest (5 min) was performed before administration of 0.1 mg.kg−1 intravenous morphine and repeated 30 min later. Patients were systematically asked questions regarding symptoms of orthostatic intolerance in each position during mobilisation. Patients not able to complete mobilisation due to intolerable orthostatic intolerance symptoms were classified as having severe orthostatic intolerance, while patients completing mobilisation despite orthostatic intolerance symptoms were classified as having non-severe orthostatic intolerance. Continuous arterial blood pressure and cerebral oxygenation were measured by LiDCO™Rapid and MasimoRoot® (Masimo, Irvine, CA, USA), respectively. The ECG was recorded continuously using CNAP®Monitor (CNSystems Medizintechnik GmbH, Graz, Austria) and heart rate variability (HRV) data were extracted and analysed using Cardiscope software (Smart Medical, Moreton in Marsh, UK) (online Supporting Information Appendix S1). The primary outcome was the incidence of orthostatic intolerance 30 min after morphine administration. Secondary outcomes were changes in haemodynamic, tissue oxygenation and HRV variables during mobilisation, before and after morphine administration. Specific data on sample size and statistics are presented in online Supporting Information Appendix S1. Before morphine administration, no patients experienced orthostatic intolerance symptoms during mobilisation. However, after intravenous administration of 0.1 mg.kg−1 morphine, 9 (38%) patients (95%CI 19–59%) experienced at least one orthostatic intolerance symptom during mobilisation at 30 min. Four (17%) patients (95%CI 5–37%) experienced severe orthostatic intolerance, terminating the mobilisation procedure prematurely due to intolerable orthostatic intolerance symptoms or pre-syncope. Two of these required treatment with ondansetron and ephedrine, respectively. There were no significant differences in patient characteristics grouped by orthostatic tolerance (online Supporting Information Table S1). Relative increases in heart rate during mobilisation were significantly attenuated in all orthostatic intolerance (p = 0.009), severe orthostatic intolerance (p = 0.027) and non-severe orthostatic intolerance patients (p = 0.042), compared with orthostatic tolerant patients, as shown in Fig. 1. Relative changes in systolic, diastolic, mean arterial pressure and cerebral oxygenation during mobilisation showed a non-significant declining trend in severe orthostatic intolerance patients (p ≥ 0.062), as shown in Table 1. Absolute HRV values in the standing position after morphine administration are presented in online Supporting Information Table S2. We observed an increased response in total autonomic power-i, low frequency-i and high frequency-i in orthostatic intolerance and non-severe orthostatic intolerance patients in standing position, compared with orthostatic tolerant patients (p ≤ 0.015). We found that postoperative treatment with opioids may be an important contributing factor to the development of postoperative orthostatic intolerance, independent of other peri-operative factors, such as inflammation, anaesthesia, hypovolaemia and pain. We found a high orthostatic intolerance incidence (38%) after pre-operative morphine administration, in line with previous studies investigating the effect of postoperative opioids on orthostatic intolerance [6, 7]. More importantly, 17% of patients could not complete the mobilisation procedure due to intolerable orthostatic intolerance symptoms. The impact of opioids on orthostatic intolerance is clinically relevant, as prolonged postoperative immobilisation likely increases the risk of postoperative complications and delayed discharge. Opioids favour parasympathetic, over sympathetic, dominance, resulting in cardiovascular depressant effects, bradycardia being the predominant effect. In line with this, we found impaired heart rate responses during mobilisation in orthostatic intolerance patients after morphine administration, as well as increased parasympathetic outflow (HF-i) using HRV analysis. We believe this is a novel and primary pathophysiological mechanism in orthostatic intolerance development, together with previously described postoperative vasoplegia [8]. Surprisingly, total autonomic power and sympathetic outflow (LF-i) were increased in the standing position in orthostatic intolerance patients, suggesting autonomic sympathetic compensation. However, sympathetic overactivation due to impending surgery might have confounded our measurements. In conclusion, morphine may be an important contributory factor to postoperative orthostatic intolerance. As opioid use is common in postoperative pain management, our findings highlight the necessity for further research looking at opioid-sparing multimodal analgesia. This study was registered at Clinicaltrials.gov (NCT04902222). AH and BU-H share first authorship. This work has been presented in part at Hvidovre Hospital's Research Day 2022, EBPOM 2022, London and DASAIM 2022, Copenhagen. Funding kindly provided by CANDYS Foundation. No other competing interests declared. Figure S1. Study flow chart. Table S1. Characteristics of orthostatic tolerant, non-severe orthostatic intolerant and severe orthostatic intolerant patients during mobilisation. Table S2. Absolute heart rate variability data during mobilisation procedure after morphine in orthostatic tolerant, orthostatic intolerant, non-severe orthostatic intolerant and severe orthostatic intolerant patients in standing position. Appendix S1. Heart rate variability analysis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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