The protocol for this systematic review was registered with PROSPERO, (International Prospective Register of Systematic Reviews, CRD42021239510), and this review is presented according to the PRISMA statement. We included randomised controlled trials (RCTs) in adult patients (≥ 18 years) undergoing surgery following a fracture to the proximal femur. Unpublished trials were eligible if trial data and methodological descriptions could be provided either in written form or through direct contact with the authors. Trials using quasi-randomisation and observational studies were excluded.
We included trials comparing single shot or continuous (catheter based) US-PNBs to conventional pain management (systemic use of opioids, NSAID/paracetamol) with or without a sham block (injection of saline) or to PNBs performed with guidance from nerve stimulation, anatomical landmarks or both. The intervention, i.e. the US-PNB, had to be administered before surgery and therefore all trials comparing PNBs given during or after surgery were excluded. Only the following PNBs were included: femoral nerve block, fascia iliaca compartment block (both superior and inferior to the inguinal ligament) and 3-in-1 block. We included trials where the US-PNB was performed with only US-guidance or combined with nerve stimulation (dual-guidance).
We searched MEDLINE (Pubmed), Embase (OVID), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, CINAHL and International Web of Science until June 16th, 2021. The full search string, developed for MEDLINE using MeSH terms and keywords related to two concepts; hip fractures and nerve blocks, is presented in the supplementary material (Appendix A). The search was not limited to contain “ultrasonography” as a concept to ensure that we would not omit any trials that failed to mention block technique in the title or abstract, neither did we limit the initial search to trials registered as randomised controlled trials. Additionally, a hand search of bibliographic references and citations of the studies that met our inclusion criteria as well as the relevant systematic reviews was conducted to ensure as high a saturation as possible. Only trials reported in Latin alphabets were included. We used Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia, 2021) for data management. In the process of selecting trials, two authors (OE and one of CS; CR; KL or LHL) independently screened the titles and abstracts yielded by the search and excluded based on our eligibility criteria. Two authors (OE and one of CS; CR; KL or LHL) then examined the full-text reports and extracted data on a predefined standardised paper form. Any disagreements between the two authors were resolved by discussion and - if necessary - a final decision was made by a third author (LHL or KL).
2.1 Primary outcome
Primary outcome was pain after block placement measured before surgery. We used preoperative pain scores as either visual analogue scale (VAS) score or numeric rating scale (NRS) score closest to two hours after intervention to minimise the range of time points and clinical heterogeneity. If pain scores were reported both at rest and at movement, we would include pain at movement in our assessments.
2.2 Secondary outcomes
Secondary outcomes were: 1) Opioid analgesic usage before surgery (measured as iv. morphine equivalents); 2: Time to first request for additional analgesia; 3: Prevalence of serious adverse events. We defined serious adverse events according to the International Conference on Harmonisation Guidelines (ICH 1995) as: "any event that leads to death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability, and any important medical event, which may jeopardise the patient or requires intervention to prevent it". All other adverse events were considered non-serious; 5: Patient satisfaction; 6: Prevalence and severity of delirium; 7: Length of hospitalisation/length of stay; 8: Mortality. We used the longest follow-up data from each trial.
We evaluated the validity and design characteristics of each trial by evaluating the trials for major sources of bias. Two authors independently used the risk of bias approach described in the Cochrane Handbook for Systematic Reviews of Interventions as a tool for assessing risk of bias in the included trials. The following risk of bias domains were assessed: allocation sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other bias like sponsor bias. These seven domains were judged to be either high risk, low risk or unclear and the trial was deemed to be in overall high risk of bias if one or more of the domains were high risk.
2.3 Statistical analysis
We used Review Manager (RevMan 5.4) software to conduct all statistical analyses following the guidelines set out by the Cochrane Handbook. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for dichotomous variables (binary outcomes) and calculated mean difference with 95% CI for continuous outcomes. The primary outcome ‘pain after block placement’ was continuous, but different scoring scales might have been used. In case of non-convertible scoring scales, we calculated the standardised mean difference (SMD). If trials reported median with corresponding ranges/interquartile ranges, the values were converted into mean with standard deviation for our meta-analyses. We planned the following sensitivity analyses of our primary outcome: 1) Evaluation of the impact of trials with high or uncertain risk of bias versus trials with low risk of bias. 2) Evaluation of the impact of US-PNBs versus PNBs without US-guidance. 3) Evaluation of the impact of the use of US-PNBs versus conventional pain treatment with or without sham block. Further, we planned the following subgroup analyses: 1) Use of US-PNBs versus PNBs without US-guidance (comparisons of subgroups of femoral nerve block vs fascia iliaca compartment block). 2) Use of US-PNBs versus conventional pain treatment with or without sham block (comparisons of subgroups of femoral nerve block vs fascia iliaca compartment block).
The degree of heterogeneity observed in the results was quantified using an inconsistency factor (I2) statistic, which can be interpreted as the proportion of the total variation observed between the trials that is attributable to differences between trials rather than sampling error (chance). The I2 statistic suggests thresholds for low (25–49%), moderate (50–74%) and high (≥ 75%) heterogeneity. We used the Chi2 test to provide an indication of heterogeneity between studies, with P ≤ 0.10 considered statistically significant.
Meta-analysis was visualised by a forest plot showing point estimates of mean and 95% CI. If I2 = 0, we would report the results from the fixed-effect model. In the case of I2 > 0, we would report the results from the random-effects model.
We used the GRADE system to evaluate quality of evidence for specific outcomes. The quality of evidence considers: (1) within study risk of bias (methodological quality); (2) directness of evidence; (3) heterogeneity of data; (4) precision of effect estimates; and (5) risk of publication bias. In GRADE there are four levels of certainty of evidence: Very low (the true effect is probably markedly different from the estimated effect); Low (the true effect might be markedly different from the estimated effect); Moderate (the true effect is probably close to the estimated effect); High (the true effect is probably similar to the estimated effect).