Early mobilisation enhances recovery and minimises postoperative complications,1,2 and is a fundamental component of current multimodal fast-track surgery protocols.3 One remaining obstacle limiting early mobilisation in the immediate postoperative period is orthostatic intolerance,4 which affects up to 60% of patients in the early postoperative period.5–9 It is characterised by symptoms such as dizziness, nausea, vomiting, feeling of heat, blurred vision and ultimately syncope.10 Orthostatic intolerance has been described after a variety of surgical procedures,5–9,11–14 including total hip arthroplasty (THA), wherein 42 and 19% of patients experienced orthostatic intolerance 6 and 24 h after surgery, respectively.7
Although not a new phenomenon, relatively little attention has been given to its causation, prevention or treatment, and available solutions are lacking.15 A few prospective studies have explored the pathogenesis of orthostatic intolerance.5,7,12,13 Together, their findings suggest that orthostatic intolerance is primarily due to postoperative autonomic nervous system dysfunction, resulting in impaired baroreflex control and a subsequent decrease in the normal vasopressor response to the postural challenge of mobilisation.12
Studies examining potential risk factors for orthostatic intolerance are limited and the existing studies6,8,9 are largely retrospective in nature. These studies have shown in multivariate analyses that female sex is associated with orthostatic intolerance in patients undergoing video-assisted thoracic surgery and gastrectomy,8,9 advanced age (≥75 years) is associated with orthostatic intolerance in video-assisted thoracic surgery8 and opioid (fentanyl) administration for patient-controlled analgesia (PCA) is associated with orthostatic intolerance in gynaecological laparoscopic surgery.6 Information on other potential risk factors for orthostatic intolerance is limited, but may include pain-induced vasovagal reflexes, antihypertensive medications (theoretically increasing the risk of postoperative hypotension)15 and gabapentin use, for which dizziness is a common side effect.16,17 Although the incidence of orthostatic intolerance after THA has been identified, few studies have investigated potential risk factors for its development.
The objectives of this study were to establish the incidence of orthostatic intolerance after THA, investigate a range of possible risk factors that may predict the occurrence of orthostatic intolerance and investigate the effects of orthostatic intolerance on hospital length of stay (LOS).
Materials and methods
This prospective observational study explored the incidence of orthostatic intolerance 24 h after surgery, and possible risk factors for its development and was approved by the local hospital research committee (RM0980713076). No written informed consent was required.
Setting and participants
Consecutive patients aged 18 years and older, undergoing unilateral THA at North Shore Hospital, Auckland, New Zealand, between May and September 2015 were included. Patients were excluded if they had revision surgery or bilateral THA.
Anaesthesia, analgesia and surgery
Surgical and anaesthetic techniques followed a standardised enhanced recovery after surgery (ERAS) approach. Surgical procedures were standardised to similar surgical approaches (lateral) and similar implants (Accolade 2; Stryker, Kalamazoo, Michigan, USA). Patients were encouraged to continue all medications until the day of surgery, whilst angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were stopped 24 h pre-operatively. Patients were encouraged to take clear fluids up to 2 h pre-operatively. Patients did not receive sedative or analgesic premedication. Regional anaesthesia was provided by single shot subarachnoid block using 0.5% bupivacaine. General anaesthesia was delivered using either total intravenous anaesthesia or inhalational anaesthesia. Intra-operative analgesia consisted of intravenous fentanyl or morphine, along with intravenous parecoxib 40 mg and paracetamol at the time of anaesthesia induction. Ketamine, clonidine and gabapentin were not routinely administered intra- or postoperatively but could be prescribed if first-line analgesia agents were ineffective (e.g. inadequate response to two repeated doses of opioid or significant adverse effects that occurred from administered opioid). Doses were not standardised but were adjusted according to patient age and comorbidity. Intra-operative hypotension was treated with fluids and vasopressors (metaraminol and ephedrine). Maintenance Plasmalyte (PL148) (Baxter Healthcare Ltd, Auckland, New Zealand) was administered at 10 to 15 ml kg−1 total volume, whilst blood loss was replaced by Gelofusine (B Braun Ltd, Auckland, New Zealand) or red blood cells with a transfusion minimum threshold of 7 g l−1. Fluid requirement was assessed clinically. Postoperative analgesia consisted of regular paracetamol, nonsteroidal anti-inflammatory medications (diclofenac, naproxen, etoricoxib), tramadol and opioids (either oral morphine or intravenous PCA morphine). Postoperative nausea and vomiting were treated using a standard treatment protocol consisting of ondansetron, cyclizine, dexamethasone and/or droperidol. Patients usually had their intravenous lines disconnected before transfer to the ward unless they had a PCA device, whilst wound drains and urinary catheterisation were not routine. All patients had wound infiltration with ropivacaine 0.2% and adrenaline (150 to 200 ml). Tranexamic acid was given to all patients.
Patients were asked to verbally rate their pain intensity using the numerical rating scale (NRS 0 to 10; 0 = no pain, 10 = worst pain imaginable) at rest and their peak pain intensity during the mobilisation procedure on the first postoperative day. A median split was used to separate patients into low pain and high pain during mobilisation. Data on patient characteristics, whether patients were mobilised out of bed on the same day as their surgery or not, as well as duration of surgery, blood loss, pre- and postsurgery haemoglobin levels (measured in the morning on the first postoperative day, i.e. same day as the orthostatic intolerance assessment), anaesthesia and analgesia in the first 24 h after surgery, postoperative nausea and vomiting, pre- and postsurgery antihypertensive drug agents and classification were retrieved retrospectively from the medical record. Postoperative opioid consumption was calculated for each patient from the time surgery finished until the patient was mobilised on the first postoperative day. Total opioid dose was converted into oral morphine equivalent daily dose (oMEDD), using the FPM (Faculty of Pain Medicine) ANZCA (Australian and New Zealand College of Anaesthetists) opioid dose equivalence calculator (http://fpm.anzca.edu.au/documents/opioid-dose-equivalence.pdf). Total oMEDD dose for each patient was then divided by the number of hours from surgery to orthostatic intolerance assessment to get an average amount (mg) per hour for each patient.
Presence or absence of orthostatic intolerance was evaluated at the first physiotherapy assessment on the first postoperative day, approximately 24 h after surgery. All patients attempted mobilisation out of bed with the physiotherapist. As this was an observational, pragmatic study that aimed to mirror clinical practice, patients were mobilised according to standardised ward/ERAS guidelines. The mobilisation procedure involved the patient going from lying supine in bed, to sitting on the side of the bed with feet resting on the floor, to standing using a walker marching on the spot, to walking with a walking aid. Presence of orthostatic intolerance on the first postoperative day was evaluated with a standardised symptom checklist, developed for the purpose of this study (appendix 1, http://links.lww.com/EJA/A185) and based on the defined symptoms characterising orthostatic intolerance (i.e. dizziness, nausea, vomiting, feeling of heat, blurred vision and ultimately syncope).10 The described symptoms have also been used as the basis for identification in previous studies.5–9,11,18 If any of the defined symptoms occurred during the mobilisation challenge, and were sufficiently severe that the mobilisation procedure had to be terminated, this was defined as orthostatic intolerance. LOS was extracted from the medical record after patient discharge.
Choice of predictor variables was based upon previous literature concerning orthostatic intolerance (Table 1). Predisposing risk factors for orthostatic intolerance were first compared between orthostatic intolerant and orthostatic tolerant patients using the Chi-square or Fisher exact test (where appropriate) for categorical variables. Continuous variables were evaluated for normal distribution and compared between orthostatic intolerant and orthostatic tolerant groups using the independent-samples t-test for normally distributed data or the Mann–Whitney U-test for variables not following the normal distribution. Categorical variables are reported as number (%) and continuous variables reported as mean (±SD) or median with IQR as appropriate. All variables with a P-value of 0.1 or less from univariate testing were included in a multivariate binary logistic regression model. A blockwise scheme was utilised to assess the model as each variable was added. The model was evaluated on the basis of changes to the -2 Log likelihood (-2LL). Hosmer and Lemeshow test and Nagelkerke R Square provided measures of poorness of fit and effect size, respectively. ORs with 95% CIs were calculated. LOS in orthostatic intolerant patients versus orthostatic tolerant patients was investigated with the Mann–Whitney U-test. All statistical analyses were carried out in SPSS version 24.0 (IBM Corp., Armonk, New York, USA), with a two-sided P value of 0.05.
A total of 151 patients underwent unilateral THA surgery during the study period, which determined the sample size. One patient in the orthostatic tolerant group had a LOS of 30 days due to a period of partial weight bearing for 4 weeks. LOS data from this patient were excluded in the final analysis. Further exclusions were 12 patients in whom the physiotherapist did not complete the form for the research study, seven patients who were transferred to an ICU/high dependency unit and 15 patients who were not mobilised at the time of physiotherapy assessment (patient declined, was too drowsy), leaving data from 117 eligible patients for analysis. Six pain scores were not recorded at the time of mobilisation and were assigned the median peak pain score of 5. Patient characteristics and differences in peri-operative factors in the orthostatic intolerant and orthostatic tolerant groups are reported in Table 1.
Patients had a mean (SD) age of 69.0 (9.7) years, and 56.4% (n = 66) were women. Between surgery and orthostatic tolerance assessment, patients received a median (IQR) oMEDD of 1.17 (0.69 to 1.87) mg h-1. Most commonly used drugs were oxycodone, followed by morphine and tramadol. Over two-thirds of patients also received opioids intravenously via PCA (most commonly morphine). Before surgery, 59.8% (n = 70) of patients were on regular medical treatment for hypertension, and this did not differ between orthostatic intolerant and orthostatic tolerant patients. Of those taking regular antihypertensive agents, 42.9% (n = 30) had at least one of their regular agents withheld in the early postoperative period.
Mobilisation and incidence of orthostatic intolerance
Median (IQR) time from surgery to first assessment by physiotherapist was 22.2 (19.4 to 25.5) h, and did not differ between orthostatic intolerant and orthostatic intolerant patients (P = 0.48). At this time point, 22.2% (n = 26) of patients demonstrated orthostatic intolerance to a degree where mobilisation had to be terminated. Symptoms associated with orthostatic intolerance were dizziness (85%, n = 22), nausea (50%, n = 13), feeling of heat (27%, n = 7), vomiting (11%, n = 3), syncope (8%, n = 2) and blurred vision (8%, n = 2). Half (n = 13) of the patients who experienced orthostatic intolerance had to terminate the mobilisation procedure while in a standing or walking position, whereas 42% (n = 11) were not able to achieve a standing position (i.e. mobilisation was terminated while in a sitting position). Despite our own hospital/ERAS guidelines recommending same day mobilisation, over half of the patients (55.6%, n = 65) in our cohort were not mobilised out of bed on the day of surgery. However, this did not differ between orthostatic intolerant and orthostatic tolerant patients (P = 0.51).
Results of the between group analysis are presented in Table 1. Patients who developed orthostatic intolerance had a higher peak pain during mobilisation (P < 0.001) and were more likely to have taken gabapentin between surgery and the time of orthostatic intolerance assessment (P = 0.01). There was a trend for orthostatic intolerance to occur more frequently in women (P = 0.07).
All three of the above-mentioned variables were retained in the logistic regression model (Model Chi-square: 17.9, P < 0.05; Hosmer and Lemeshow test: P = 0.81; Nagelkerke pseudo R2: 0.23). Odd ratios (95% CI) were female sex: 3.1 (1.0 to 9.6), P = 0.048; postoperative use of gabapentin: 3.6 (1.2 to 10.2), P = 0.018; and high peak pain levels (≥5/10) during mobilisation: 4.1 (1.3 to 12.6), P = 0.016. Overall, 78% of patients were correctly identified as having or not having orthostatic intolerance. The model was more accurate at predicting those who would not get orthostatic intolerance (89% correct), compared with those who did have the condition (39% correct).
Length of stay
There was a significant difference in LOS between orthostatic intolerant and orthostatic tolerant patients (P = 0.019). The median [IQR] LOS was 3.5 [3 to 4.75] days for orthostatic intolerant patients versus 3 [2 to 4] days for orthostatic tolerant patients.
This study found that orthostatic intolerance was present in more than one in five patients approximately 24 h after surgery, to a degree where the mobilisation procedure had to be terminated. Our results support previous findings that orthostatic intolerance is significant and common in the immediate postoperative period,5–9,11,18 and is similar to that found by Jans et al. (19% at 24 h) with THA.7 Second, we examined a broad range of potential risk factors for orthostatic intolerance and found female sex, postoperative use of gabapentin and high peak pain levels during mobilisation to be independent predictors of orthostatic intolerance.
Although previous prospective studies did not focus on patient-related factors,15 female sex was an independent risk factor for orthostatic intolerance in two previous retrospective studies (video-assisted thoracic surgery8 and gastrectomy9). The association between female sex and orthostatic intolerance is consistent with existing research identifying sex differences in autonomic function and blood pressure regulation. Recent findings19 revealed that men immediately showed a marked and sustained increase in sympathetic activity to compensate for an orthostatic challenge, whereas sympathetic activity in women only increased slightly, with delayed onset, and without significantly affecting sympathovagal balance. Sex differences have also been investigated in space research,20 wherein data suggest that the higher incidence of orthostatic intolerance in female astronauts may be related to increased lower limb venous compliance, contributing to blood pooling upon standing.20 Other studies21–23 have shown that women respond to cardiovascular stress with greater heart rate increases through parasympathetic withdrawal, whereas men respond primarily with greater increases in vascular resistance through sympathetic control of peripheral vasoconstriction.
Although chronic pre-existing orthostatic hypotension/orthostatic intolerance increases with advancing age,24 and age has previously been reported to be a risk factor for orthostatic intolerance in video-assisted thoracic surgery,8 age was not identified as a risk factor in our study. The association with age and orthostatic intolerance has also been examined in retrospective studies in patients undergoing gastrectomy9 and gynaecological laparoscopy procedures,6 and like the present study, was not found to be a risk factor.
Pain scores in our study were considerably higher; median [IQR] 7 [5 to 8], compared with previous THA studies assessing pain in relation to orthostatic intolerance at 24 h (2 [2 to 3] and 2 [0.5 to 3.5]).7,18 However, we recorded the peak pain rating at any time during the mobilisation procedure, whereas other studies reported pain ratings on standing, which may account for at least some of the difference. Pain ratings have also been compared between orthostatic intolerant and orthostatic tolerant patients in prostatectomy,5,11 breast cancer surgery13 and gastrectomy.9 No differences in pain ratings between orthostatic intolerant and orthostatic tolerant patients were found in these studies. However, from a physiological viewpoint, strong nociceptive input can trigger a direct hypothalamic activation of the medullary cardiovascular centres, causing a vasovagal response.25 High pain may also be associated with anxiety or fear during mobilisation, which are other known triggers for the vasovagal response,25 and may in turn exacerbate or contribute to orthostatic intolerance.
Adding gabapentin to a multimodal regimen does not appear to significantly reduce acute pain or opioid consumption after THA.26,27 Although gabapentin is not routinely administered for THA in our hospital, nearly half of the patients in this study did receive gabapentin as part of ‘rescue analgesia’. Importantly, gabapentin between surgery and the time of mobilisation was found to be an independent predictor of orthostatic intolerance (i.e. after controlling for pain during mobilisation). Dizziness is one of the most common side effects of gabapentin,17 and may be relevant for development of orthostatic intolerance, although the precise aetiology is unclear. This has also been found in a knee arthroplasty population, with higher rates of dizziness and visual disturbance found in patients taking 1300 mg day-1 of gabapentin in the postoperative period but no difference in pain scores.28 Previous prospective studies7,18 investigating orthostatic intolerance following THA routinely administered gabapentin pre- and postsurgery, which may have played a role in the development of orthostatic intolerance although this was not investigated further.
It is thought that both opioids and antihypertensive medications can have an effect on orthostatic intolerance. However, we found no difference in administered opioid use (oral dose, use of PCA or total dose) between orthostatic intolerant and orthostatic tolerant patients. This is consistent with the findings from a small prospective study, using multimodal opioid-sparing analgesia, wherein no difference in oral opioid dose was found between orthostatic intolerant and orthostatic tolerant patients following THA.7 In contrast, retrospective studies of patients having gastrectomy, video-assisted thoracic surgery and gynaecological laparoscopy procedures found that opioid administration (continuous infusion of fentanyl) was independently associated with orthostatic intolerance in multivariate analyses.6,8,9 It should be noted that pre-operative opioid use was not taken into account in our study. It is possible that postoperative opioid dose and its effects on orthostatic intolerance may differ between regular opioid users and those who were opioid-naive at the time of surgery.
The majority of patients in our study were on regular treatment for hypertension, taking single or multiple antihypertensive agents. Nearly half of those patients had one or more of their agents withheld in the immediate postoperative period due to hypotension. Several different combinations of agents and withholding of some agents in the early postoperative period makes comparisons of specific agents and their potential role in the risk of developing orthostatic intolerance during early postoperative mobilisation difficult. However, we could find no evidence that the use of antihypertensives increased the risk of orthostatic intolerance in our cohort.
Limitations of this study are its single-centre design and relatively small sample size, which increase the risk that the lack of association between orthostatic intolerance and some factors (e.g. opioid dose) may be due to type II error. Secondly, the timing of the first physiotherapy mobilisation/assessment could not be at the same time postsurgery for all patients. However, the timing between surgery and first physiotherapy assessment did not differ between orthostatic intolerant and orthostatic tolerant patients. Thirdly, rescue analgesia administration and intravenous fluid supplementation was not standardised but given according to individual clinical evaluation and patient response. However, this pragmatic, observational approach can also be viewed as a strength, as it reflected standard practice, thus enhancing the clinical relevance of our findings. We also did not assess the extent of postoperative inflammation in our cohort, which may be involved in the pathogenesis of orthostatic intolerance.15 However, a recent randomised controlled trial has shown that high-dose methylpredlisone does not reduce the incidence of orthostatic intolerance 24 h after THA, despite a strongly attenuated inflammatory response.29 Finally, we chose not to use physiological criteria of orthostatic hypotension [decrease in systolic arterial pressure (30 mmHg)],18 for terminating the mobilisation procedure, as orthostatic hypotension is often asymptomatic5,30 and orthostatic intolerance symptoms that are sufficiently severe to prevent mobilisation is what is most clinically relevant. This conjecture is supported by our finding of an increased LOS in the orthostatic intolerant group, consistent with a previous study after prostatectomy.11 Although the increase in LOS in our study was modest, considering the high incidence rates of orthostatic intolerance in other major surgical procedures,5,6,8,9,11 even a small increase in LOS has the potential to significantly increase hospital-related costs.
Orthostatic intolerance is common on the first postoperative day following THA, affects patients’ ability to mobilise and was associated with an increased LOS. In our cohort, orthostatic intolerance was more common in women, in patients given gabapentin postoperatively and in patients with high peak pain scores during attempted mobilisation. Overall, our model was much better at identifying orthostatic tolerant patients (89%) with relatively poor accuracy in identifying orthostatic intolerant patients (39%). This suggests that there is substantial variability in the development of orthostatic intolerance that cannot be explained by female sex, gabapentin use or high pain scores alone. This may reflect a combination of factors related to underlying physiological differences, surgical variations, medication use and/or psychological factors (e.g. postoperative fear or anxiety). As such, personalised recovery pathways appear attractive, but at present, the ability to predict individuals at risk of orthostatic intolerance is still limited.
Acknowledgements relating to this article
Assistance with the study: the authors would like to thank the physiotherapists at Waitemata District Health Board who assisted in postoperative data collection.
Financial support and sponsorship: no external funding received. M. Skarin was funded by a personal and limited research grant from Waitemata District Health Board.
Conflicts of interest: none.
Presentation: preliminary data presented at the ANZCA (Australian and New Zealand College of Anaesthetists) annual scientific meeting 2016, Auckland, 30 April to 4 May, and at the Physiotherapy NZ conference 2016, Auckland 16 to 18 September.
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