Click here to watch a video clip showing transurethral enucleation and resection of the prostate technique

Despite the availability of numerous minimally invasive techniques, transurethral resection of the prostate (TURP) remains the most common surgical treatment for lower urinary tract symptoms (LUTS) caused by benign prostatic enlargement (BPE) in small to medium-sized prostates.1 Nonetheless, TURP has been associated with significant complication rates.2

Bipolar TURP uses saline irrigation, which decreases the risk of TURP syndrome compared with monopolar TURP, and both bipolar and monopolar TURP result in comparable functional outcomes.3 The bipolar system can also be broadened to enucleate the prostate gland along the surgical capsule, using a resectoscope combined with a loop. This transurethral enucleation and resection of the prostate (TUERP) technique can potentially remove more prostatic tissue than TURP and requires no additional devices.

In the present study, we describe the technique and early postoperative outcomes of bipolar TUERP and compare our results with major international series.

Between January 2014 and June 2014, 28 consecutive patients underwent bipolar TUERP at Kwong Wah Hospital, Hong Kong. All patients were evaluated preoperatively by physical examination, digital rectal examination, transrectal ultrasonography (TRUS) of the prostate, and laboratory studies that included measurement of haemoglobin, sodium, and prostate-specific antigen (PSA). Patients were offered the option of ultrasound-guided transrectal prostate biopsy if the PSA level was >4 ng/mL or if the digital rectal examination showed suspicion of prostate cancer. Abnormal digital rectal examination findings included prostate nodule, asymmetry of the lateral lobes, or irregularity of the prostate. The TRUS was performed to measure the maximum length, width, and anteroposterior height of the prostate to calculate the prostate volume using the ellipse formula, where prostate volume (mL) = 0.52 x length x width x height. Patient baseline characteristics, indications for surgery, and operative data and complications were recorded by doctors. Patients with neurogenic bladder, previous genitourinary tract surgery, urethral stricture, or known bladder or prostate carcinoma were excluded from the technique of bipolar TUERP.

All bipolar TUERP procedures were performed by a single surgeon. This surgeon had performed 37 TUERPs using various techniques and devices previously, before the procedure was standardised as described below and shown in Figure 1. The technique used in this report was first described by and adopted from Prof CX Liu at Zhujiang Hospital of Southern Medical University in Guangzhou.4

Antiplatelet medications were stopped 3 days prior to surgery. Patients received general or spinal anaesthesia and were placed in the lithotomy position. Bladder stones where present were fragmented with a holmium laser via a 21-Fr rigid cystoscope and were evacuated with an Ellik evacuator before bipolar TUERP. A 26-Fr Olympus SurgMaster TURis resectoscope (Olympus Europe, Hamburg, Germany) with a standard loop was used. The incision was begun immediately proximal to the verumontanum using a cutting current. The surgical capsule plane was identified, and the whole gland dissected in a retrograde fashion from the cleavage plane using the resectoscope sheath, until the circular fibres of the bladder neck were identified. The loop electrode was used to coagulate all of the denuded vessels immediately during the detachment process. The adenoma was subtotally enucleated with a narrow pedicle attached to the bladder neck at the 6 o’clock position. The devascularised adenoma was rapidly resected in pieces by the loop electrode. The bladder neck at 5 to 7 o’clock was removed if it appeared relatively high. The anterior commissure at 12 o’clock was preserved except when it appeared obstructive endoscopically. The chips were evacuated with an Ellik evacuator. Finally, the prostatic fossa was inspected and haemostasis secured. A 24-Fr three-way urethral catheter was inserted at the end of the procedure for bladder irrigation. One of the patients in the series had open inguinal hernia repair performed after bipolar TUERP. Haemoglobin level and serum sodium concentration were measured on the same day after surgery. The protocol for postoperative care following bipolar TUERP was the same as that for monopolar and bipolar TURP in our unit. Bladder irrigation was stopped the following morning, and the catheter was removed on the second day postoperatively.

All patients were evaluated following bipolar TUERP during clinic visits at 4 weeks and 3 months. At each visit, history, physical examination, International Prostate Symptom Score (IPSS), and TRUS of the prostate were evaluated. The presence or absence of transient urinary incontinence was documented with direct questioning of the patient. Uroflowmetry was performed at 8 weeks, and serum PSA levels were measured at 3 months.

Table 1 lists the patients’ baseline characteristics, operative data, and early postoperative outcomes. Enucleation time was defined as the time from incision to completion of subtotal enucleation of the adenomatous tissue. Resection time was defined as the time needed for fragmentation of the en-bloc adenoma into chips. The mean enucleation and resection times were 13.6 (median, 15; range, 10-30) minutes and 47.7 (median, 35; range, 15-120) minutes, respectively, with a mean of 48.2 g of adenoma resected.

The mean PSA level decreased from 6.4 ng/mL to 0.9 ng/mL at 3 months postoperatively, representing an 85.9% decrease. Pathological examination of enucleated tissue revealed prostatic adenocarcinoma in one patient who had T1a disease with a Gleason score of 6; the serum PSA level decreased from 4.6 ng/mL to 1.7 ng/mL in this patient. There was a significant decrease in mean TRUS volume from 71.9 cm³ to 22.9 cm³ at 4 weeks and to 15.1 cm³ at 3 months postoperatively, corresponding to decreases of 68.2% and 79.0% at 4 weeks and 3 months, respectively.

More than half of the patients in our series (16 of 28 patients) presented with refractory acute urinary retention or obstructive uropathy and had required catheterisation prior to surgery. Preoperative uroflowmetry within the last year was available in only 15 patients, thus comparison between preoperative and postoperative urodynamic parameters was less representative. The mean peak urinary flow rate was 20.9 mL/s, and the mean post-void residual was 31.6 mL at 8 weeks postoperatively. The mean IPSS was 9.4, and the mean quality-of-life score was 1.9 at 4 weeks.

There was no requirement for blood transfusion nor incidence of clot retention in any patient. The mean decrease in haemoglobin was 11.5 g/L. Urinary tract infection presenting as acute epididymitis was noted in two (7.1%) patients. One (3.6%) patient required re-catheterisation on day 2 postoperatively and was successfully weaned off the catheter on day 5. Transient urinary incontinence was noted in three patients and one patient at 1 and 3 months postoperatively, respectively (10.7% at 1 month and 3.6% at 3 months). An average of two incontinence pads were required daily, and all cases of transient urinary incontinence subsided within 4 months. No urethral stricture, meatal stenosis, or bladder neck contracture was noted at 3 months.

The TURP has been considered the standard surgical therapy for LUTS caused by BPE. Despite improvements in equipment and techniques over the years, TURP remains associated with significant morbidity and re-treatment rates, particularly in patients with a large prostate.5 Open prostatectomy (OP) is therefore still considered a valid option for patients with a prostate of >80 g.6

Surgical enucleation for the treatment of LUTS caused by BPE remains the most complete method to remove adenomas of any size; the history of surgical enucleation dates back more than 100 years.7 In spite of the low re-operation rate and high success rate, OP is an invasive procedure associated with higher transfusion rates, longer catheterisation time, and longer hospital stay. As a result, the popularity of OP has declined.

The concept of surgical enucleation was revisited with the advent of endoscopic alternatives to open enucleation. Endoscopic enucleation allows for maximal removal of the adenoma and results in potentially equivalent efficacy compared with its open counterpart, with significantly lower morbidity. Holmium laser enucleation of the prostate (HoLEP) was the first endoscopic enucleative technique described.8 This technique has been compared with OP and TURP in various randomised controlled trials, yielding at least comparable outcomes and a favourable safety profile.9 The use of expensive high-energy holmium laser equipment and a steep learning curve, however, have limited the extensive application of HoLEP worldwide. There has also been a significant risk of bladder injury associated with the use of the mechanical tissue morcellator that is required for HoLEP.

The use of normal saline as an irrigant was made possible by the introduction of bipolar devices. As a result, the risk of TURP syndrome has been virtually eliminated, and bipolar TURP has been widely adopted for resection of larger prostates with longer operating times. The use of a bipolar device in endoscopic enucleation was first reported by Neill et al,10 and bipolar TUERP requires no additional devices in comparison with bipolar TURP. Moreover, the sheath of the resectoscope is used for mechanical enucleation of the adenoma along the plane of the surgical capsule, instead of the holmium laser used in HoLEP. The subtotally enucleated adenoma is then resected into chips by the loop electrode, and the use of a mechanical tissue morcellator is eliminated.

The nomenclature for this procedure has not been standardised, with terms such as TUERP, plasmakinetic enucleation of the prostate, and bipolar plasma enucleation of the prostate reported in the literature. All of these names generally refer to the same procedure with minor differences. The term ‘bipolar TUERP’ is used in this article.

Several modifications in technique and equipment since the introduction of bipolar TUERP have been suggested. For example, a spatula-like enucleation loop, combined with a loop electrode for haemostasis, was introduced by Olympus and is especially designed for this procedure. Alternatively, the use of thick loop electrodes and button electrodes has been described in some series to facilitate the enucleation process. Based on personal experience with these different loops, the alternative loops with different designs are generally stronger than the conventional loop electrode, and they can be used for mechanical enucleation without breakage. The use of the loop in performing enucleation, instead of the resectoscope sheath, also provides better, more direct visualisation during the enucleation process and potentially shortens the learning curve and improves the safety of the procedure, particularly in the early phase of learning. The resectoscope sheath, however, facilitates a shorter enucleation time without compromising safety with the surgeon’s experience. The initial technique adopted for bipolar TUERP was the ‘three-lobe’ technique. This procedure starts with deep incisions down to the surgical capsule at the 5 and 7 o’clock positions from the bladder neck to the verumontanum, with an additional incision at the 12 o’clock position also reported. The median and lateral lobes of the prostate are then subtotally enucleated and resected in sequence. Some authors have reported ‘hybrid’ techniques, with the median lobe resected as in conventional TURP and only the lateral lobes enucleated. It has also been noted that deep incisions might not be necessary, as the surgical capsule plane can generally be identified with a small incision immediately proximal to the verumontanum, and the whole gland can be enucleated without separation of the lobes. This procedure avoids the bleeding associated with deep incisions of the bladder neck and adenoma although a small lobe can sometimes be difficult to enucleate after separation of the lobes. The 12 o’clock incision has been mostly abandoned, as has also been advocated for HoLEP. The anterior commissure, particularly the distal part, has been preserved to decrease the rate of transient urinary incontinence postoperatively. The technique used in our centre is currently the most widely practised among different centres.

Several series have reported the perioperative outcomes of bipolar TUERP using similar surgical techniques. Only the largest series from each centre was included for comparison; most of the published series are from China. The results of our series were compared with the TUERP arms of the various published series; this list of series and a comparison of the preoperative parameters are listed in Table 2. After the first published article by Neill et al10 comparing HoLEP and bipolar TUERP in 2006, Liu et al11 published the largest series with 1600 patients in 2010. Zhao et al12 and Liao and Yu13 followed by comparing bipolar TUERP and TURP in medium-sized prostates. Kan et al14 compared bipolar TUERP and TURP in large prostates, and Rao et al,15 Ou et al,16 Geavlete et al,17 and Chen et al18 compared bipolar TUERP with OP. The operative and early postoperative outcomes of bipolar TUERP from various studies are listed in Table 3.

The operating time was generally longer when the preoperative TRUS volume and resected prostate weight increased. Although Liu et al11 reported enucleation and resection times without reporting the total operating time, the preoperative TRUS volume and resected prostate weight were comparable between Liu et al’s report11 and our series. In addition, the resection time was prostate-size–dependent, and a resection efficacy of approximately 1 g/min was reported in both Liu et al’s report11 and our series. The enucleation time was less size-dependent, varying from 10 to 30 minutes, despite the large range of prostate sizes in our series.

The decrease in haemoglobin of approximately 10 g/L was reported for both medium-sized and large prostates. Early control of denuded vessels during the enucleation process made the removal of large glands possible, with minimal blood loss during the resection process.

The catheterisation and hospitalisation times varied greatly among the series evaluated. Longer times for both have typically been reported in series from China.11 12 13 15 16 18 In addition, no standard protocols were stated in most of the series, and the decision for catheter removal and hospital discharge were at the discretion of the surgeons. We report short catheterisation and hospitalisation times with the adoption of the same protocol as TURP in our institution. Specifically, bladder irrigation was stopped on postoperative day 1, the catheter was removed, and the patient was discharged from the hospital on postoperative day 2. A total of 92.9% of the patients (26 of 28 patients) complied with the postoperative protocol.

Postoperative TRUS volume was rarely reported by the series despite the consistent reporting of preoperative volume. This lack of reporting reflects the difficulty in accurately estimating residual tissue volume by TRUS, as illustrated by the postoperative TRUS photo shown in Figure 2. In addition, the central cavity remaining after TUERP can lead to overestimation of the prostate volume with the application of the traditional ellipse formula. Instead, preoperative estimation of the peripheral zone volume, obtained by subtracting the volume of the central zone from the total prostate volume, may represent a better method for estimating the residual tissue volume after TUERP. A decrease in TRUS volume of approximately 70% after TUERP was consistently reported, despite the pitfalls of postoperative TRUS measurements.

It has also been shown from the experience of HoLEP that a reduction in PSA level correlated with the amount of prostate tissue removed.19 Thus, serum PSA may serve as a better surrogate marker in the estimation of postoperative residual tissue volume. A postoperative PSA level of approximately 1 ng/mL and a decrease in PSA by >70% were commonly reported in most of the series.

Adverse events were poorly and inconsistently reported, as shown in Table 4. The standard Clavien classification was not adopted. There was no Clavien grade 3 or 4 complication in our series. The transfusion rate was low, with the exception of the series by Ou et al,16 and clot retention was rare. The rate of urinary tract infection ranged from 2% to 7.3%, and the re-catheterisation rate was <5%. Major complications were not common but did occur, as reported by Kan et al14; four admissions to intensive care units and nine conversions to other procedures were reported in this series of 74 patients. The rate of urethral stricture or bladder neck stenosis was low and comparable with conventional TURP as reported by the series by Liu et al.11 Long-term outcome was not reported in our series due to the short duration of follow-up. Temporary urinary incontinence was the major concern with enucleative procedures, and OP resulted in temporary urinary incontinence in approximately 10% of cases. The reporting of transient urinary incontinence after TUERP was poor and did not feature in three of the nine series analysed. Furthermore, the definition, timing, and severity of urinary incontinence were not stated in the other studies. Dramatic changes in the symptomatology of the patients over time following benign prostatic hyperplasia–related surgery, however, likely explain the difficulty in defining transient urinary incontinence. In our experience, transient urinary incontinence is not uncommon after TURP, although it is difficult to differentiate the type of urinary incontinence, stress, urge or mixed, by history or urodynamic studies. The natural history of this phenomenon has rarely been reported in the literature. It was interesting to note that the rate of transient urinary incontinence was much higher for the TURP group (16.1%) compared with the TUERP group (7.5%) in the series by Liao and Yu.13 In our experience, 17.9% of patients reported episode(s) of urinary incontinence at any time point after TUERP; the rate of transient urinary incontinence was 10.7% and 3.6% at 1 and 3 months postoperatively, respectively. Patients who had transient urinary incontinence used two pads daily on average, and all cases of transient urinary incontinence subsided by 4 months. Further investigations with, for example, measurement of pad weight and urodynamic studies will better delineate the cause and natural history of postoperative transient urinary incontinence. There is currently no predictive factor identified for the phenomenon.

Comparison of outcome and complications between patients with and without urinary retention was limited by the small patient number in our study. No significant difference between outcome and complications was identified even though patients with retention were significantly older.

A learning curve of 50 cases was reported for HoLEP,20 and this learning curve was expected to be shorter for bipolar TUERP. The instrumentation for TUERP should be familiar to an endourologist experienced in TURP because no additional devices are required. Xiong et al21 analysed the learning curve of bipolar TUERP. The ratio of conversion to conventional TURP decreased after 30 cases, and the efficiency of enucleation and resection increased with accumulative experience after 50 cases. Our series showed that the early postoperative outcomes were comparable to those of large series after approximately 35 cases, without an increase in adverse events. The findings were based on analysis of the learning curve of a single surgeon and may not be applicable to all surgeons. Nevertheless, an estimation of a learning curve in a magnitude of 30 to 50 cases seems reasonable and serves as a valuable reference.

Our study suggests that bipolar TUERP is a safe technique for prostates of any size. This procedure should become the endourological equivalent to open adenomectomy, with fewer complications and shorter convalescence. This technique can also be acquired safely with a relatively short learning curve.

1. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol 2003;170:530-47. Crossref

2. Madersbacher S, Lackner J, Brössner C, et al. Reoperation, myocardial infarction and mortality after transurethral and open prostatectomy: a nation-wide, long-term analysis of 23,123 cases. Eur Urol 2005;47:499-504. Crossref

3. Mamoulakis C, Ubbink DT, de la Rosette JJ. Bipolar versus monopolar transurethral resection of the prostate: a systematic review and meta-analysis of randomized controlled trials. Eur Urol 2009;56:798-809. Crossref

4. Liu C, Zheng S, Li H, Xu K. Transurethral enucleative resection of prostate for treatment of BPH. Eur Urol 2006;5 Suppl:234. Crossref

5. Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of transurethral resection of the prostate (TURP)—incidence, management, and prevention. Eur Urol 2006;50:969-79; discussion 980. Crossref

6. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2013;64:118-40. Crossref

7. Freyer PJ. Total enucleation of the prostate. A further series of 550 cases of the operation. Br Med J 1919;1:121-120.2.

8. Gilling PJ, Kennett KM, Fraundorfer MR. Holmium laser enucleation of the prostate for glands larger than 100 g: an endourologic alternative to open prostatectomy. J Endourol 2000;14:529-31. Crossref

9. Ahyai SA, Gilling P, Kaplan SA, et al. Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol 2010;58:384-97. Crossref

10. Neill MG, Gilling PJ, Kennett KM, et al. Randomized trial comparing holmium laser enucleation of prostate with plasmakinetic enucleation of prostate for treatment of benign prostatic hyperplasia. Urology 2006;68:1020-4. Crossref

11. Liu C, Zheng S, Li H, Xu K. Transurethral enucleation and resection of prostate in patients with benign prostatic hyperplasia by plasma kinetics. J Urol 2010;184:2440-5. Crossref

12. Zhao Z, Zeng G, Zhong W, Mai Z, Zeng S, Tao X. A prospective, randomised trial comparing plasmakinetic enucleation to standard transurethral resection of the prostate for symptomatic benign prostatic hyperplasia: three-year follow-up results. Eur Urol 2010;58:752-8. Crossref

13. Liao N, Yu J. A study comparing plasmakinetic enucleation with bipolar plasmakinetic resection of the prostate for benign prostatic hyperplasia. J Endourol 2012;26:884-8. Crossref

14. Kan CF, Tsu HL, Chiu Y, To HC, Sze B, Chan SW. A prospective study comparing bipolar endoscopic enucleation of prostate with bipolar transurethral resection in saline for management of symptomatic benign prostate enlargement larger than 70 g in a matched cohort. Int Urol Nephrol 2014;46:511-7. Crossref

15. Rao JM, Yang JR, Ren YX, He J, Ding P, Yang JH. Plasmakinetic enucleation of the prostate versus transvesical open prostatectomy for benign prostatic hyperplasia >80 mL: 12-month follow-up results of a randomized clinical trial. Urology 2013;82:176-81. Crossref

16. Ou R, Deng X, Yang W, Wei X, Chen H, Xie K. Transurethral enucleation and resection of the prostate vs transvesical prostatectomy for prostate volumes >80 mL: a prospective randomized study. BJU Int 2013;112:239-45. Crossref

17. Geavlete B, Stanescu F, Iacoboaie C, Geavlete P. Bipolar plasma enucleation of the prostate vs open prostatectomy in large benign prostatic hyperplasia cases—a medium term, prospective, randomized comparison. BJU Int 2013;111:793-803. Crossref

18. Chen S, Zhu L, Cai J, et al. Plasmakinetic enucleation of the prostate compared with open prostatectomy for prostates larger than 100 grams: a randomized noninferiority controlled trial with long-term results at 6 years. Eur Urol 2014;66:284-91. Crossref

19. Tinmouth WW, Habib E, Kim SC, et al. Change in serum prostate specific antigen concentration after holmium laser enucleation of the prostate: a marker for completeness of adenoma resection? J Endourol 2005;19:550-4. Crossref

20. Shah HN, Mahajan AP, Sodha HS, Hegde S, Mohile PD, Bansal MB. Prospective evaluation of the learning curve for holmium laser enucleation of the prostate. J Urol 2007;177:1468-74. Crossref

21. Xiong W, Sun M, Ran Q, Chen F, Du Y, Dou K. Learning curve for bipolar transurethral enucleation and resection of the prostate in saline for symptomatic benign prostatic hyperplasia: experience in the first 100 consecutive patients. Urol Int 2013;90:68-74. Crossref

Intussusception is the most common cause of intestinal obstruction in infants and young children between the age of 3 months and 3 years, and the peak age of presentation is 4 to 8 months.1 The invagination of proximal bowel into more distal bowel results in venous congestion and bowel wall oedema. If this condition is not promptly diagnosed and treated, arterial obstruction and bowel necrosis and perforation may occur.2 Approximately 90% of intussusceptions in the paediatric age-group are ileocolic and idiopathic,3 presumably caused by lymphoid hyperplasia that has been suggested as the ‘lead point’ in its pathogenesis.4 Viral infection may also play a role.5 6 7 8

The reported incidence of a pathological lead point in paediatric intussusception is approximately 6%,9 the most common of which is Meckel’s diverticulum.10 Systemic conditions such as Henoch-Schönlein purpura, Peutz-Jeghers syndrome, and familial polyposis can also increase the risk of intussusception. Abdominal trauma and postoperative abdomen have also been reported to pose a higher risk for intussusception.11 12 13 14

The presenting symptoms of intussusception are often non-specific and may mimic viral gastro-enteritis, presenting as vomiting and diarrhoea. The classic triad of red currant jelly stool, abdominal pain, and abdominal mass is not often encountered, and the diagnosis may easily be delayed or missed.15 Plain abdominal films are neither sensitive nor specific for intussusception and may be completely normal.16 The most consistent finding is a paucity of gas in the right iliac fossa. Other possible features include soft tissue mass, target sign, or meniscus sign.17 The first-line investigation for diagnosis of intussusception in children is abdominal ultrasound, given its high sensitivity (98%-100%) and specificity (88%-100%).18

Non-operative reduction methods for intussusception include barium enema, and hydrostatic or pneumatic reduction.19 Pneumatic reduction is currently the preferred standard treatment, given the greater ease of performing the examination, the lesser morbidity with complications, and the slightly higher success rate of 84% to 100%.20 21 22

Operative reduction is required when non-operative reduction is either contra-indicated (eg peritonitis, perforation, profound shock) or unsuccessful. Open surgery has been the conventional approach although laparoscopic reduction is also feasible and successful in uncomplicated cases.23 24

In this study, we aimed to review our hospital’s experience in the management of paediatric intussusception over the last 17 years, with a focus on assessing the efficacy of non-operative reduction and identifying the risk factors that may lower its success rate.

We conducted a retrospective study of children who presented with intussusception from January 1997 to December 2014 in our hospital. We started with the year 1997 as some of earlier records were incomplete. Patient demographics, clinical presentation, duration of symptoms, treatment modalities, complication rate, and length of hospital stay were studied. The method of non-operative reduction in our institution was ultrasound-guided hydrostatic reduction before 2005 and pneumatic reduction with fluoroscopy after 2005, as the latter was easier and faster to perform. The procedure was performed by paediatric radiologists, with a paediatric surgeon available if necessary. In pneumatic reduction, air is insufflated via a Foley catheter (with size of 18-Fr to 22-Fr, depending on patient’s size, with balloon inflated with 10 mL water) placed inside the patient’s rectum under pressure monitoring at 120 mm Hg. Our radiologists would perform a maximum of three attempts. The patient might be given intravenous midazolam at a dose of 0.1 to 0.2 mg/kg if necessary. Successful reduction was demonstrated by free flow of air into the terminal ileum and disappearance of the caecal soft tissue mass.

For laparoscopic reduction, a 5-mm subumbilical port was used for camera access. Another two working ports (one in the upper and one in the lower abdomen) were inserted. Reduction of intussusception was performed with laparoscopic graspers. In open reduction, manual reduction was achieved by milking the intussusceptum out of the intussuscipient. Bowel resection was performed when bowel necrosis was found intra-operatively.

Data analysis was carried out using the Statistical Package for the Social Sciences (Windows version 21.0; SPSS Inc, Chicago [IL], US). Mean values were expressed with standard deviation. Continuous variables were compared with Mann-Whitney U test and categorical values with Chi squared test. Results were considered statistically significant when P≤0.05. Comparison of success, recurrence, and complication rates between hydrostatic and pneumatic reduction groups was performed. The length of hospital stay was also compared.

A total of 173 children (108 male, 65 female) presented to our hospital with intussusception during the study period. Of them, 83 (48%) were admitted directly to our paediatric surgical ward, 50 (29%) were referred from the paediatric medical ward in our hospital, and the remaining 40 (23%) were referred from other public and private hospitals. The median age at presentation was 12.5 months (range, 2 months to 16 years) and the mean (± standard deviation) duration of presenting symptoms was 2.3 ± 1.8 days. The common presenting symptoms and their percentage of occurrence are shown in Table 1. The most common symptom reported was vomiting and occurred in 132 (76.3%) patients.

All patients except one were diagnosed by ultrasonography. One patient underwent computed tomographic scan for diagnosis due to an atypical presentation of intussusception. All patients underwent either non-operative or operative treatment within 24 hours of admission. Pneumatic or hydrostatic reduction (Fig a) was performed in 160 patients, among which 127 (79.4%) were successful and three (1.9%) were complicated by bowel perforation. A total of 46 patients in our study required operative reduction, but two of the intussusceptions were found to be reduced upon laparotomy. These radiological misdiagnoses could be due to mistaken identity of the oedematous ileocaecal valve for intussusceptum. The indications for operative treatment are summarised in Table 1. Early recurrence of intussusception (<72 hours post-reduction) occurred in four (3.1%) of the 127 patients who had initial successful non-operative reduction. No recurrence was reported in patients treated surgically. Laparoscopic reduction was attempted in 13 patients, among whom five (38.5%) were successful. Conversion to open reduction was required in five patients because of the need for bowel resection and in a further three due to difficult reduction. Among the 46 patients who required operative reduction, 23 (50%) required bowel resection. A pathological lead point was noted intra-operatively in seven (15.2%) patients and four had a perforated bowel (three of which were complications of non-operative reduction). The remaining 12 had non-viable gangrenous bowel that was subsequently confirmed by histology. The operations were complicated with one burst abdomen and one anastomotic leak. The age distribution in our cohort of patients and the number of patients with pathological lead point are shown in Table 2.

We next analysed the possible risk factors for unsuccessful non-operative reduction in the 160 patients (Table 3). The only statistically significant factor was the presence of an abdominal mass (relative risk=2.0; 95% confidence interval, 1.8-2.2). The distribution of the duration of symptoms is presented in Table 4. Nonetheless, the duration of symptoms and the extent of the intussusception did not appear to affect the chance of a successful non-operative reduction (Table 5). There were 129 patients with intussusception at the hepatic flexure or a more proximal site, 93 (72.1%) of whom had successful non-operative reduction; 44 presented with intussusception at the transverse colon or a more distal site, of whom 34 (77.3%) underwent successful non-operative reduction. There was no significant difference in the success rate of non-operative reduction between the two groups (P=0.56). Approximately 50% of patients were admitted directly to our ward from the beginning. There was no difference in the success rate of non-operative reduction between this group of patients and those who were referred from other wards or hospitals (77.1% vs 77.3%, P=1.00).

The overall success rate of non-operative reduction was 79.4%. We also compared the success rate for the two non-operative treatment modalities. There was no statistically significant difference between the success rate of hydrostatic reduction (81.5%) versus pneumatic reduction (77.2%) in our study (P=0.56).

There was a statistically significant difference in the median length of post-reduction hospital stay for patients who were successfully treated non-operatively (3 days; range, 1-12 days) versus operatively (7.5 days; range, 3-73 days; P=0.01).

Intussusception is a true paediatric surgical emergency and is second only to appendicitis as the most common cause of an acute abdominal emergency in children.25 The complete classic triad of intermittent abdominal pain, red currant jelly stool, and a palpable abdominal mass is not a common presentation.26 Only five (2.9%) of our patients were documented to have all three symptoms present at the time of hospital admission. In accordance with previous studies, vomiting was the most common presenting symptom.4 27 Per rectal bleeding or red currant jelly stool signify bowel ischaemia and mucosal sloughing but is a rather late sign and was present in only 40.5% of our patients. Nonetheless, all except one patient had at least one of the symptoms of abdominal pain, abdominal mass, red currant jelly stool, vomiting, or irritability. These symptoms should be actively sought in any patient in whom intussusception is suspected.

The most reliable abdominal sign, if present, is a palpable mass in the right upper quadrant of the abdomen. It was present in 39.3% of our patients, and was a risk factor for the need of operative treatment. We postulate that a palpable mass may signify relatively longer duration of intussusception that causes complete intestinal obstruction, thus rendering non-operative reduction less successful as it becomes more difficult for the reduction medium to pass through. Many children with intussusception present with non-specific signs and symptoms, thus the diagnosis may easily be delayed or missed.15 Therefore, as clinicians we must maintain a high index of suspicion in order to identify this emergency in a timely manner. Early referral of suspected cases to a tertiary treatment centre can significantly reduce morbidity in the child.

With positive sonographic findings of intussusception, an enema is reserved for therapeutic purposes, although it may be necessary for diagnosis when ultrasonography findings are questionable. Computed tomography is seldom needed for diagnosis of paediatric intussusception, except in cases where an associated underlying pathological lead point is suspected. Our recommended diagnostic and treatment algorithm is summarised in Figure b. Pneumatic reduction is currently our preferred standard treatment of intussusception, given the greater ease of performing the examination, lesser morbidity with complication, and the high success rate.20 21 22 Major advantages of air enema reduction include a relatively low radiation dose and improved safety with constant pressure monitoring.28 29 The perforation rate is reported to be less than 3%.30 In a randomised trial performed by Hadidi and El Shal,22 pneumatic reduction was concluded to be the modality with fewest complications and highest success rate, when compared with barium enema and hydrostatic reduction. In our study, there was no statistically significant difference in the success rate between hydrostatic reduction and pneumatic reduction (81.5% vs 77.2%, P=0.56). We believe that this is attributable to the fact that both hydrostatic and pneumatic reductions are based on similar principles.

Laparoscopic reduction has been demonstrated to be feasible and successful in uncomplicated intussusception.23 24 In our series, five (62.5%) of the eight conversions from laparoscopic to open reduction were due to the need for bowel resection.

Non-operative reduction has a high overall success rate and low complication and recurrence rates. A high success rate was observed even in the group of patients with delayed presentation of over 72 hours. It also leads to a shorter hospital stay and is therefore recommended as the first-line treatment of this condition.

The presence of a palpable abdominal mass is a risk factor for failure of non-operative reduction. Operative intervention should not be delayed in these patients who encounter difficult or doubtful non-operative reduction. For patients in whom non-operative reduction fails, laparoscopic reduction appears to be a feasible option. From our experience, a significant proportion of this group of patients require bowel resection. If the viability of the bowel is doubtful during laparoscopy, early conversion to open surgery should be performed in order to avoid delay in treatment.

Non-operative reduction has a high success rate and low complication rate, but the presence of a palpable abdominal mass is a risk factor for failure. Operative intervention should not be delayed in these patients who encounter difficult or doubtful non-operative reduction.

1. Bines J, Ivanoff B. Acute intussusception in infants and children: incidence, clinical presentation and management: a global perspective. Report 02.19. Geneva: World Health Organization; 2002.

2. Stringer MD, Pablot SM, Brereton RJ. Paediatric intussusception. Br J Surg 1992;79:867-76. Crossref

3. Bajaj L, Roback MG. Postreduction management of intussusception in a children’s hospital emergency department. Pediatrics 2003;112:1302-7. Crossref

4. DiFiore JW. Intussusception. Semin Pediatr Surg 1999;8:214-20. Crossref

5. Mayell MJ. Intussusception in infancy and childhood in Southern Africa. A review of 223 cases. Arch Dis Child 1972;47:20-5. Crossref

6. Mangete ED, Allison AB. Intussusception in infancy and childhood: an analysis of 69 cases. West Afr J Med 1994;13:87-90.

7. Asano Y, Yoshikawa T, Suga S, Hata T, Yamazaki T, Yazaki T. Simultaneous occurrence of human herpesvirus 6 infection and intussusception in three infants. Pediatr Infect Dis J 1991;10:335-7. Crossref

8. O’Ryan M, Lucero Y, Peña A, Valenzuela MT. Two year review of intestinal intussusception in six large public hospitals of Santiago, Chile. Pediatr Infect Dis J 2003;22:717-21. Crossref

9. Blakelock RT, Beasley SW. The clinical implications of non-idiopathic intussusception. Pediatr Surg Int 1998;14:163-7. Crossref

10. Navarro O, Dugougeat F, Kornecki A, Shuckett B, Alton DJ, Daneman A. The impact of imaging in the management of intussusception owing to pathologic lead points in children. A review of 43 cases. Pediatr Radiol 2000;30:594-603. Crossref

11. Komadina R, Smrkolj V. Intussusception after blunt abdominal trauma. J Trauma 1998;45:615-6. Crossref

12. Stockinger ZT, McSwain N Jr. Intussusception caused by abdominal trauma: case report and review of 91 cases reported in the literature. J Trauma 2005;58:187-8. Crossref

13. Türkyilmaz Z, Sönmez K, Demiroğullari B, et al. Postoperative intussusception in children. Acta Chir Belg 2005;105:187-9.

14. Emil S, Shaw X, Laberge JM. Post-operative colocolic intussusception. Pediatr Surg Int 2003;19:220-2.

15. Reijnen JA, Festen C, Joosten HJ, van Wieringen PM. Atypical characteristics of a group of children with intussusception. Acta Paediatr Scand 1990;79:675-9. Crossref

16. Hernandez JA, Swischuk LE, Angel CA. Validity of plain films in intussusception. Emerg Radiol 2004;10:323-6.

17. Ratcliffe JF, Fong S, Cheong I, O’Connell P. The plain abdominal film in intussusception: the accuracy and incidence of radiographic signs. Pediatr Radiol 1992;22:110-1. Crossref

18. Bhisitkul DM, Listernick R, Shkolnik A, et al. Clinical application of ultrasonography in the diagnosis of intussusception. J Pediatr 1992;121:182-6. Crossref

19. Peh WC, Khong PL, Lam C, et al. Reduction of intussusception in children using sonographic guidance. AJR Am J Roentgenol 1999;173:985-8. Crossref

20. Lui KW, Wong HF, Cheung YC, et al. Air enema for diagnosis and reduction of intussusception in children: clinical experience and fluoroscopy time correlation. J Pediatr Surg 2001;36:479-81. Crossref

21. Rubí I, Vera R, Rubí SC, et al. Air reduction of intussusception. Eur J Pediatr Surg 2002;12:387-90. Crossref

22. Hadidi AT, El Shal N. Childhood intussusception: a comparative study of nonsurgical management. J Pediatr Surg 1999;34:304-7. Crossref

23. Schier F. Experience with laparoscopy in the treatment of intussusception. J Pediatr Surg 1997;32:1713-4. Crossref

24. Poddoubnyi IV, Dronov AF, Blinnikov OI, Smirnov AN, Darenkov IA, Dedov KA. Laparoscopy in the treatment of intussusception in children. J Pediatr Surg 1998;33:1194-7. Crossref

25. Waseem M, Rosenberg HK. Intussusception. Pediatr Emerg Care 2008;24:793-800. Crossref

26. Bruce J, Huh YS, Cooney DR, Karp MP, Allen JE, Jewett TC Jr. Intussusception: evolution of current management. J Pediatr Gastroenterol Nutr 1987;6:663-74. Crossref

27. Losek JD. Intussusception: don’t miss the diagnosis! Pediatr Emerg Care 1993;9:46-51. Crossref

28. Stringer DA, Ein SH. Pneumatic reduction: advantages, risks and indications. Pediatr Radiol 1990;20:475-7. Crossref

29. Meyer JS, Dangman BC, Buonomo C, Berlin JA. Air and liquid contrast agents in the management of intussusception: a controlled, randomized trial. Radiology 1993;188:507-11. Crossref

30. Daneman A, Alton DJ, Ein S, Wesson D, Superina R, Thorner P. Perforation during attempted intussusception reduction in children—a comparison of perforation with barium and air. Pediatr Radiol 1995;25:81-8. Crossref

Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical.1 Traditionally, diagnosis in these patients relies on extensive endocrine investigation. With advances in the understanding of the genes involved in sexual determination and differentiation,2 molecular diagnosis is playing an increasingly important role and may even overtake the role of hormonal assessment as the first-line test, with the latter being reserved for assessment of disease severity rather than diagnosis.3

One of the most common causes of 46,XY DSD in the western population is androgen insensitivity syndrome (AIS).4 Whether the same is true in our local population remains unknown. We performed a prospective multicentre study to explore the possible aetiological basis of 46,XY DSD in the Hong Kong Chinese population.

Patients who were referred to a paediatric endocrinologist for the first time or were followed up in their clinic at five public hospitals in Hong Kong between July 2009 and June 2011 were recruited for the study. Inclusion criteria were 46,XY ethnic Chinese patients who presented with incompletely virilised, ambiguous, or completely female external genitalia. Criteria that suggested DSD at birth were overt genital ambiguity, apparent female genitalia with an enlarged clitoris, posterior labial fusion, or an inguinal/labial mass, apparent male genitalia with bilateral undescended testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testes, and discordance between genital appearance and prenatal karyotype.1 Micropenis is defined as stretched penile length of <2.5 cm based on the published norm for Chinese.1 Written informed consent was obtained from the patients and/or parents and the study was approved by the local ethics committee. None of the patients/parents refused to participate in the study although seven refused genetic testing (Table 1).

Blood was taken from patients for electrolyte and baseline endocrine assessment and included measurement of cortisol, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate, testosterone (T), androstenedione (A4), dihydrotestosterone (DHT), anti-Müllerian hormone (AMH), and gonadotropins. Human chorionic gonadotropin (hCG) stimulation test was performed to test for testicular Leydig cell function. The short synacthen test was also performed when indicated.

Cortisol, dehydroepiandrosterone sulfate, and gonadotropins were measured by electro-chemiluminescence immunoassay (Modular Analytics E170; Roche, Mannheim, Germany); T was measured by a competitive immunoenzymatic assay (ACCESS 2; Beckman Coulter, Brea [CA], US); 17-OHP was measured by liquid chromatography–tandem mass spectrometry using an in-house method; AMH was measured by an enzyme-linked immunosorbent assay (AMH Gen II ELISA, A73818; Beckman Coulter, Brea [CA], US); DHT was measured by radioimmunoassay (DSL9600i; Beckman Coulter, Prague, Czech Republic); A4 was measured by solid-phase competitive chemiluminescent enzyme-labelled immunoassay (L2KAO2, Immulite 2000; Siemens, Tarrytown [NY], US). Male reference intervals were considered the most appropriate for data interpretation in this study.

Spot urine from patients under 3 months of age and 24-hour urine from those at or older than 3 months of age were processed for steroid profiling as described previously.5

DNA was extracted from peripheral whole blood using a QIAamp DNA blood kit (Qiagen, Hilden, Germany). Polymerase chain reaction and direct DNA sequencing were performed on targeted genes when suggested by the clinical and hormonal findings. Otherwise all patients had their AR (androgen receptor) and NR5A1 (steroidogenic factor 1) genes sequenced. Those patients with negative genetic findings were subjected to multiplex ligation-dependent probe amplification (MLPA) analysis (P185 Intersex probemix; P074 Androgen Receptor probemix and P334 Gonadal probemix; MRC-Holland) to test for gross deletion or gene duplication. The results were analysed by Coffalyser.Net. Family genetic studies were performed when mutation(s) were identified in the index patients.

The functional effect of novel missense mutations detected was tested by online in-silico analysis software SIFT, PolyPhen2, and Align GVGD.

Overall, 64 patients (53 male, 11 phenotypic female), including 14 new patients, with 46,XY DSD were recruited into the study. The clinical and hormonal findings of individual patients are listed in Table 1. A genetic diagnosis was made in 10 patients prior to the study. Other major structural abnormalities were evident in eight (Table 2). Their age at presentation ranged from birth to 17 years. Five (8%) were born prematurely (24-35 weeks) and nine (14%) with low birth weight (0.59-2.32 kg). All had non-consanguineous parents. A family history of sexual ambiguity was present in six. Overall, 61 (95%) presented with ambiguous external genitalia including 15 with isolated micropenis, eight with isolated severe hypospadias, and one with discordance between the prenatal karyotype and the postnatal phenotype. Three presented after birth, one each with inguinal hernia, delayed puberty, and primary amenorrhoea.

Regarding the hormonal findings, Figure 1 shows the baseline and post-hCG–stimulated T and DHT levels in patients with mutations detected in the AR gene and those without, where the results overlapped between the two groups. Eight patients (patients 13, 19, 21, 30, 31, 40, 49, and 56) underwent short synacthen test and with the exception of patient 19, all had an adequate cortisol response (>550 nmol/L). Patient 27 had a relatively low T/A4 ratio before and after hCG stimulation but sequencing revealed no mutation in his HSD17B3 (17β-hydroxysteroid dehydrogenase III) gene. All other patients had unremarkable T and A4 levels, as well as T/A4 ratio.

Eleven patients had characteristically low 5α- to 5β-reduced steroid metabolite ratios in their urine, compatible with the diagnosis of 5α-reductase 2 deficiency (5ARD). This was also confirmed by mutational analysis of the SRD5A2 (steroid 5α-reductase 2) gene. All other patients had unremarkable urinary steroid metabolite pattern.

Overall, 22 (39%) patients had a confirmed genetic diagnosis (Table 3). The most common diagnoses in our cohort were 5ARD (n=11) and AIS (n=7). Other genetic diagnoses included cholesterol side-chain cleavage enzyme deficiency (n=1), Frasier syndrome (n=1), NR5A1-related sex reversal (n=1), and persistent Müllerian duct syndrome (PMDS; n=1). The clinical and laboratory findings of patients 19 and 20 have been reported previously.6 7 Patients 12 and 15 had de-novo mutations in the AR gene and were in mosaic pattern. Patient 21 had a novel missense variant p.Ala260Val detected in his NR5A1 gene. His AMH level was not low, contrary to some of the previously reported cases.8 There was also a clinically significant rise in T level after hCG stimulation. Short synacthen test demonstrated an adequate cortisol response (baseline: 720 nmol/L; post–adrenocorticotropin hormone: 822 nmol/L). His father also carried the same heterozygous mutation although he denied any symptoms of DSD. This novel genetic variant was not detected in 100 normal Chinese subjects (control). Patient 22 had bilateral undescended testes. He underwent orchidopexy at the age of 1 year during which the presence of Müllerian duct structures was suspected. Further workup including pelvic ultrasound revealed Müllerian duct structures and extremely low AMH level. The diagnosis of PMDS was confirmed by the presence of three heterozygous novel missense variants in the AMH gene (Tables 3 and 4).

Six novel genetic variants were identified in the AMH, AR, and NR5A1 genes (Fig 2). At least two of the three in-silico analysis programmes predicted the variants to be pathogenic (Table 4). Multiple sequence alignment showed that the amino acids of concern were highly conserved across different animal species. All these findings support the pathogenic nature of these variants accounting for the patients’ phenotypes.

Eleven patients were reared as girls because of severe under-virilisation at birth, including three with 5ARD, three with AIS, and one with Frasier syndrome. The underlying genetic causes in the remaining four patients were undetermined. The longest follow-up period was 27 years. None of them has requested change of gender to date. Five patients (patients 2, 4, 7, 12, and 15) exhibited ‘tom-boy-like’ behaviour during childhood and required counselling by a clinical psychologist while two males (patients 17 and 47) requested exogenous T to augment penile growth after puberty. Patient 20 developed germinoma in her dysgenetic gonad with no recurrence after surgery.

46,XY DSD is a heterogeneous condition caused by a wide spectrum of disorders. Making an accurate diagnosis is difficult but important for emergency medical treatment as some DSDs are associated with life-threatening Addisonian crisis. In addition, the diagnosis is essential so that relevant information and counselling can be provided to parents and clinical management can be formulated, bearing in mind the best interests of the child. Initial workup includes a detailed antenatal and postnatal history, physical examination, karyotyping, and hormonal assays. This will guide further workup such as imaging and genetic analysis. Nonetheless, there are often limitations to hormonal studies as illustrated in the present series. The non-distinct pattern of T and DHT at baseline and following hCG stimulation in AR mutation–positive and –negative patients suggest the need to reconsider our laboratory diagnostic algorithm for AIS.

Androgen insensitivity syndrome is reported to be the most common cause of 46,XY DSD in a few ethnic groups,9 10 11 while 5ARD, which is believed to be rare, was also a major aetiology in our cohort. It is important to differentiate between 5ARD and AIS as soon as possible so that patients with 5ARD can be raised as boys whenever practical.12 The penile growth of patients with 5ARD can be promoted by topical DHT treatment and spontaneous virilisation may occur during puberty. Most of these patients who are reared as girls during childhood identify themselves as male and change their gender as an adult, although we have not received any such request from our cohort. Exposure to androgen during the antenatal, postnatal, and pubertal period may masculinise the brain and influence gender identity.13 It was found that 5ARD is easy to diagnose by its characteristic urinary steroid excretion pattern and its high mutational detection rate in the SRD5A2 gene.14 Of the 11 patients with 5ARD, eight harboured the missense mutation p.Arg227Gln in their SRD5A2 gene, a useful fact to enable screening for this mutation before proceeding to sequencing of the whole gene. Unfortunately, patients have previously been too easily labelled with AIS when laboratory diagnostic services were less advanced. This is illustrated by patient 7 who was labelled as AIS until her urine steroids were analysed and revealed classic features of 5ARD.15 We recommend that 5ARD is excluded in all 46,XY DSD patients before other differential diagnoses are considered. Moreover, since the baseline and post-hCG–stimulated T and DHT results are unreliable when diagnosing AIS, genetic study of the AR gene should also be performed as a first-line investigation.

HSD17B3 deficiency has been reported to be the most common cause of T biosynthetic defect leading to 46,XY DSD in some populations, with an estimated incidence of 1:147 000 in the Netherlands and as high as 1:200 to 1:300 in Arabians due to their high consanguinity rate.16 17 Nonetheless, no patient in our cohort was diagnosed with this condition based on the hormonal pattern. Ethnic differences in disease spectrum may be one of the reasons for this observation. Another possible explanation is the lack of reliable diagnostic cutoff for the pre- and post-stimulated T/A4 ratios. George et al18 have summarised the cutoffs used by various researchers, with the pre-stimulated cutoff range set at 0.006 to 1.64, and the post-stimulated level set at 0.09 to 3.4 for newborn to teenage groups. The difficulties in setting up reliable diagnostic cutoffs for the T/A4 ratio are similar to the T/DHT ratios and have been discussed in our previous study.14 Furthermore, HSD17B3 deficiency gives no characteristic findings on urinary steroid profiling.5 19 Molecular analysis of the HSD17B3 gene may have offered a means to diagnose this condition but unfortunately, due to budget constraints, we were unable to perform mutational analysis of this gene in all our patients, although a normal MLPA result in our patients made gross deletion in this gene unlikely.

The two novel mutations p.Asp266Asn and p.Thr576Pro in the AR gene lie within the N-terminal domain of the androgen receptor that is involved in transcription regulation and DNA binding, respectively. Missense mutations around these two codons have been reported in patients with AIS according to the Androgen Receptor Gene Mutations Database, April 2013.20 Multiple sequence alignment shows that both amino acids are highly conserved among different species, suggesting that aspartic acid at codon 266 and threonine at codon 576 are critical for proper receptor function. Similarly, the alanine at codon 260 of the NR5A1 gene is located in helix 3 of the ligand-binding domain of the nuclear receptor,21 and is also a highly conserved region. Mutation in this region has been reported to result in 46,XY DSD.8 Replacing alanine at this position by valine is therefore expected to be deleterious to the protein function. Phenotypic variability in NR5A1 gene mutation within a kindred has been reported and this may explain why patient 21 had ambiguous external genitalia to such an extent that he required the attention of a paediatric specialist, even though his father was fertile, and denied any symptoms of DSD or need for medical attention.22 For the AMH gene, the 3’ end of exon 5 is one of the mutational hotspots in patients with PMDS.23 Exon 5 encodes the bioactive C-terminal domain. The three mutations detected in patient 22 are all located at highly conserved regions. Although in-vitro functional characterisation for the mutant proteins was not performed, the undetectable serum AMH level in this patient was compatible with the mutations being pathogenic, possibly due to abnormal protein folding and increased instability, as reported previously in mutations located in this region.24

Gonadal malignancy was rare in our series, probably because gonadectomy was performed early in life when the decision of female sex assignment was made. Although this helps to avoid further virilisation and to establish gender identity, the timing of corrective surgery and gonadectomy remain controversial. Patient advocacy groups have suggested delaying any surgery for cosmetic reasons until the patient is mature enough to give informed consent25 but such practice has not been validated in our Chinese patients. Whether cultural factors have any impact on gender assignment remains uncertain in our community.

Prematurity or low birth weight was not uncommon in our series. This made diagnosis of DSD in our patients even more difficult because ethnic-specific and gestational age– or weight-adjusted anthropometric measurement of the external genitalia was not available. Assessment of the genital anatomy relies solely on the experience of the paediatric specialist and is obviously far from ideal. A conjoint effort by local paediatricians is needed to set up these normative data.

Less than half of our patients had a confirmed diagnosis in the present study. With the increasing availability of next-generation sequencing technology, and with its established role in molecular diagnostic services, including DSD,3 26 it is hoped that sooner rather than later, most patients will have a confirmed genetic diagnosis. Nonetheless, we speculate that some patients have a non-genetic aetiology since environmental factors may alter the phenotypic expression. Several animal and human studies have shown that antenatal exposure to pesticides and plasticisers may lead to fetal genital malformation.27

Altogether there was an average of 11 250 male live births every year in the five public hospitals that participated in this study. Since 11 newborns with 46,XY DSD were born in these five hospitals and were recruited during our study period, this gives an estimated incidence of 46,XY DSD of 1:2045 male births requiring the input of paediatric endocrinologists. This figure may underestimate the true incidence of this group of diseases as some patients present late and others may have subtle defects that go unnoticed by our specialists. If the actual number of patients with chromosomal and 46,XX DSD in our population is considered, the actual incidence of DSD can be expected to be much higher.

There are a few limitations in this study. First, the number of patients was relatively small. This may have resulted in bias in our observation and the data do not represent the prevalence of disease in our population. Second, in-vitro study was not performed on the novel genetic variants for functional characterisation, although we believe that all the available evidence indicates the pathogenic nature of these variants. Third, due to budget constraints, we were unable to sequence all genes related to 46,XY DSD.

Our findings indicate that 5ARD and AIS are possibly the major causes of 46,XY DSD in the Hong Kong Chinese population. Molecular analyses of the SRD5A2 and AR genes were demonstrated to be more reliable than hormonal testing. Since the missense mutation p.Arg227Gln was a recurrent hotspot mutation in 5ARD in our local patients, all patients should be screened for this mutation.

We thank Mr YC Ho, Ms YF Wong, and Ms YP Iu for their technical assistance. The study was supported by the Queen Elizabeth Hospital Research Grant 2009 QEH/RC/G/0910-A04/R0901 and Kowloon Central Cluster Research Grant 2012 KCC/RC/G/1213-B01.

1. Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006;118.e488-500. Crossref

2. Ono M, Harley VR. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol 2013;9:79-91. Crossref

3. Arboleda VA, Lee H, Sánchez FJ, et al. Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development. Clin Genet 2013;83:35-43. Crossref

4. Jääskeläinen J. Molecular biology of androgen insensitivity. Mol Cell Endocrinol 2012;35:4-12. Crossref

5. Chan AO, Shek CC. Urinary steroid profiling in the diagnosis of congenital adrenal hyperplasia and disorders of sex development: experience of a urinary steroid referral centre in Hong Kong. Clin Biochem 2013;46:327-34. Crossref

6. Parajes S, Chan AO, But WM, et al. Delayed diagnosis of adrenal insufficiency in a patient with severe penoscrotal hypospadias due to two novel P450 side-chain cleavage enzyme (CYP11A1) mutations (p.R360W; p.R405X). Eur J Endocrinol 2012;167:881-5. Crossref

7. Chan WK, To KF, But WM, Lee KW. Frasier syndrome: a rare cause of delayed puberty. Hong Kong Med J 2006;12:225-7.

8. Allali S, Muller JB, Brauner R, et al. Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46,XY disorders of sex development (DSD) including hypospadias. PLoS One 2011;6:e24117. Crossref

9. Bangsbøll S, Qvist I, Lebech PE, Lewinsky M. Testicular feminization syndrome and associated gonadal tumors in Denmark. Acta Obstet Gynecol Scand 1992;71:63-6. Crossref

10. Boehmer AL, Brinkmann O, Brüggenwirth H, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 2001;86:4151-60. Crossref

11. Abdullah MA, Saeed U, Abass A, et al. Disorders of sex development among Sudanese children: 5-year experience of a pediatric endocrinology clinic. J Pediatr Endocrinol Metab 2012;25:1065-72. Crossref

12. Mieszczak J, Houk CP, Lee PA. Assignment of the sex of rearing in the neonate with a disorder of sex development. Curr Opin Pediatr 2009;21:541-7. Crossref

13. Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med 1979;300:1233-7. Crossref

14. Chan AO, But BW, Lee CY, et al. Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential? Clin Chem 2013;59:798-806. Crossref

15. Chan AO, But BW, Lau GT, et al. Diagnosis of 5α-reductase 2 deficiency: a local experience. Hong Kong Med J 2009;15:130-5.

16. Boehmer AL, Brinkmann AO, Sandkuijl LA, et al. 17β-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab 1999;84:4713-21. Crossref

17. Rosler A. 17 Beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. Pediatr Endocrinol Rev 2006;3 Suppl 3:455-61.

18. George MM, New MI, Ten S, Sultan C, Bhangoo A. The clinical and molecular heterogeneity of 17βHSD-3 enzyme deficiency. Horm Res Paediatr 2010;74:229-40. Crossref

19. Lee YS, Kirk JM, Stanhope RG, et al. Phenotypic variability in 17β-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. Clin Endocrinol 2007;67:20-8. Crossref

20. Androgen Receptor Gene Mutations Database. Available from: http://androgendb.mcgill.ca/. Accessed Aug 2013.

21. El-Khairi R, Martinez-Aguayo A, Ferraz-de-Souza B, Lin L, Achermann JC. Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function. Endocr Dev 2011;20:38-46.

22. Ciaccio M, Costanzo M, Guercio G, et al. Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred. Horm Res Paediatr 2012;78:119-26. Crossref

23. Josso N, Belville C, di Clemente N, Picard JY. AMH and AMH receptor defects in persistent Müllerian duct syndrome. Hum Reprod Update 2005;11:351-6. Crossref

24. Belville C, Van Vlijmen H, Ehrenfels C, et al. Mutations of the anti-Müllerian hormone gene in patients with persistent Müllerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three-dimensional model. Mol Endocrinol 2004;18:708-21. Crossref

25. Consortium on the Management of Disorders of Sex Development: Clinical Guidelines for the Management of Disorders of Sex Development in Childhood. California, US: Intersex Society of North America; 2006. Available from: http://www.dsdguidelines.org/files/clinical.pdf. Accessed Aug 2015.

26. Hersmus R, Stoop H, Turbitt E, et al. SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype. BMC Med Genet 2012;13:108. Crossref

27. Kalfa N, Philibert PH, Baskin LS, Sultan C. Hypospadias: interactions between environment and genetics. Mol Cell Endocrinol 2011;335:89-95. Crossref

Providing professional care and establishing a good rapport with patients is the mission of all health care workers. This relationship building is part of the patient-centred health care delivery model that is currently being advocated over a clinician- or disease-centred model.1 It is associated with better clinical outcomes and may reduce potential complaints due to miscommunication.2 3 4 In the intensive care setting where patients often cannot make their own decisions, either due to their illness or to the effect of medications,5 building a good relationship with the patients’ family is especially important. Furthermore, it has been recognised that families of patients admitted to the intensive care unit (ICU) are at higher risk of developing anxiety, depression, and post-traumatic stress disorder.6 7 They are suddenly subjected to an uncertain outcome for their loved ones, with associated emotional, social and financial consequences, and in a strange environment packed with complex technological advancements. The long-term psychological impact on the family after an ICU encounter is now termed as post-intensive care syndrome–family (PICS-F).7 This adds to the society’s health care burden and reduces the family ability to provide care. Evidence suggests that the risk of developing PICS-F is affected by the manner in which health care workers interact with the family.8 For these reasons, ICU quality measurement should include the families’ perspective and their satisfaction with the care process.9 10

In early 2012, the Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Hong Kong (PYNICU) initiated the Family Satisfaction Enhancement (FAME) programme that aimed to improve family satisfaction with ICU care. A regular satisfaction survey was performed that intended to identify problem areas and make subsequent improvements. The current study was part of the FAME programme that evaluated the level of family satisfaction in a local ICU and its performance in comparison with international standards, and determined factors that are independently associated with a higher family satisfaction and could be used to plan future initiatives.

This was a questionnaire survey carried out at PYNICU, which is a mixed medical-surgical 22-bed adult ICU in a regional hospital with 1633 beds in Hong Kong. It is a closed ICU with 24-hour intensivist coverage.

The Family Satisfaction in the ICU (FS-ICU) questionnaire is a patient family satisfaction questionnaire originally developed in 2003 by a group of health care professionals in Canada: the Canadian Researchers at the End of Life Network (CARENET).5 The questionnaire has been validated for use in North America and Europe,11 12 13 14 and has been translated into other languages including Chinese. The questionnaire is accessible online (http://www.thecarenet.ca). The questionnaire consists of 37 items in two parts: satisfaction with overall ICU care, and satisfaction with decision-making around the care of critically ill patients; and three open-ended questions. Respondents were asked to provide baseline data (sex, age, relationship with the patient, prior experience with ICU, and whether they lived together before admission) at the start of the questionnaire. Corresponding patient data were retrieved from the Clinical Management System, electronic Patient Record, and Clinical Data Analysis and Reporting System.

Patients who were admitted to the ICU for 48 hours or more between 15 June 2012 and 31 January 2014, and were visited by their next-of-kin (NOK; defined as the key contact person nominated by the family and documented on the nursing chart on admission) during their stay in the ICU were eligible. Once an eligible patient was nearing ICU discharge (defined as an expected date of ICU discharge within the next 5 days as judged each morning by a senior clinician or nurse consultant), or had passed away in the ICU, his/her NOK was invited by an independent research assistant not involved in clinical care to participate in the survey. A minimum stay of 48 hours was used as in previous studies to ensure an adequate exposure of families to the ICU.15 16 A copy of the questionnaire and an envelope were given to the NOK to be completed based on his/her opinion. He/she was asked to return the questionnaire in the envelope provided, which was opened only by researchers. Those who failed to return the questionnaire were contacted by phone within 2 months of ICU discharge or death, and the questionnaire was sent to them with a stamped addressed envelope if they agreed to participate. All respondents were ensured of the confidentiality and anonymity of their response. For patients who were admitted to the ICU more than once within the same hospitalisation, only the last was analysed.

The study protocol was reviewed by the Hong Kong East Cluster Ethics Committee and the need for consent was waived.

Items in the FS-ICU questionnaire were scored as previously described12: each item was recoded into a linear scale ranging from 0 to 100, with 0 as very poor or very dissatisfied, and 100 as excellent or completely satisfied. Three items (“received appropriate amount of information”, “had enough time to think in decision-making process”, and “adequate time to address concerns and answer questions”) were recoded into dichotomous variables, while two items (“involved at right time in decision-making process”, and “given right amount of hope patient would recover”) were recoded into a 3-point Likert scale.12 A mean (± standard deviation [SD]) score was computed for each item. Subscores for satisfaction with overall ICU care (FS-ICU/Care) and satisfaction with role in decision-making (FS-ICU/DM), and a total score (FS-ICU/Total) were generated by averaging available items, provided that the respondent answered 70% or more of the items in the respective sections.12

Results were compared using Mann-Whitney U test with those of a multicentre Canadian database (written communication, Daren Heyland, Feb 2014) that comprised data captured from 2003 to 2006 at 12 Canadian sites.

Univariate analyses of satisfaction with overall ICU care and satisfaction with role in decision-making were conducted. Variables included the baseline respondent’s and patient’s characteristics, as well as items of part 1 or part 2 of FS-ICU, respectively. Continuous variables were categorised using their median, and questionnaire items were categorised into “completely satisfied” and “less than completely satisfied”. Factors with a P value of ≤0.1 were entered into multivariable logistic regression using stepwise backward elimination to identify independent factors associated with complete family satisfaction with overall ICU care and role in decision-making.

The independent factors thus identified by multivariable logistic regression were used in the construction of performance-importance plots to identify those factors that deserve more urgent attention because of their higher importance (regression weights above the median) but lower performance (percentage of that item being rated as “excellent” being below the median).

By applying the rule of 10 on logistic regression analysis of family satisfaction with overall ICU care, a target sample size was estimated to be 725 with 29 covariates with an estimated 40% of respondents being “completely satisfied” with overall care. All tests were two-sided, and a P value of <0.05 was considered statistically significant. All data were analysed using the Statistical Package for the Social Sciences (Windows version 20; SPSS Inc, Chicago [IL], US).

From 15 June 2012 to 31 January 2014, 961 patients were eligible and 822 families agreed to participate; 736 questionnaires were eventually returned, with a response rate of 76.6%. Excluding the three questions only applicable to families of patients who passed away in ICU and the three open-ended questions, 23 766 (95.0%) of the total 25 024 questions were completed. Baseline characteristics of the respondents and patients are shown in Table 1.

Our mean (± SD) FS-ICU/Total, FS-ICU/Care, and FS-ICU/DM scores were 78.1 ± 14.3, 78.0 ± 16.8, and 78.6 ± 13.6, respectively. Table 2 shows the percentage of responses and mean score for each questionnaire item.

When results were compared with the Canadian data (written communication, Daren Heyland, Feb 2014), the latter had a higher mean FS-ICU/Total, FS-ICU/Care, and FS-ICU/DM score of 82.9 ± 14.8, 83.5 ± 15.4, and 82.6 ± 16.0, respectively (P<0.001 for all three scores when compared with PYNICU). Table 2 shows the result for each FS-ICU item; PYNICU achieved a significantly higher mean score for item “control over care”. There was no significant difference in scores between the two databases for items “frequency of communication by physicians”, “atmosphere of ICU waiting room”, “involved at the right time in decision-making”, “received appropriate amount of information”, and “given right amount of hope”. The Canadian sites achieved higher scores for the remaining items.

In the univariate analysis of satisfaction with overall ICU care, none of the patient’s or respondent’s characteristics had a P≤0.1. Items “spiritual support for family”, “support from social workers”, and “support from pastors” were excluded since more than 30% of the responses were either missing or deemed not applicable. Thus, a total of 14 covariates were analysed in the multivariable analysis. The independent factors identified were “concern and caring for patients”, “agitation management”, “concern and caring for family”, “frequency of communication by nurses”, “physician skill and competence”, “atmosphere of ICU”, and “atmosphere of ICU waiting room” (Table 3). In the multivariable analysis of satisfaction with role in decision-making, 16 covariates including “age of respondent”, “sex of respondent” (with P values of 0.005 and 0.08, respectively in the univariate analysis), and all items in part two of the questionnaire excluding item “given right amount of hope” (P=0.214 in univariate analysis) were tested. Independent factors identified were “honesty of information”, “completeness of information”, “control over care”, “agreement within family regarding care patient received”, “satisfaction with amount of health care”, and “age of respondent ≥47 years” (Table 3).

Performance-importance plots identified the following items as being more important but performed less satisfactorily: “atmosphere of ICU waiting room”, “atmosphere of ICU”, “agitation management” (overall care), and “satisfaction with amount of health care” (decision-making) [Fig 1].

This is the first ICU family satisfaction survey published in Hong Kong, and was conducted following implementation of the FAME programme in 2012. Following a small-scale survey carried out by PYNICU in 2010 (written communication, HL Wu, 2012), staff awareness about the importance of family satisfaction has increased. Family satisfaction was added to the regular agenda at our weekly business meetings, where comments and feedback from NOKs were discussed. These discussions led to various measures to improve communication (unsolicited nurses’ update during visiting hours), access to information (information booklets in waiting rooms and noticeboard displays for families), and facilities (chairs for families at bedside, televisions for awake patients, and refurbishment of the waiting rooms). This survey showed high satisfaction scores in 2012 to 2014 that were similar to figures reported around the world (Fig 2 16 17 18 as well as the multicentre Canadian database—a German study reported their mean FS-ICU/Total, FS-ICU/Care, and FS-ICU/DM as 78.3 ± 14.3, 78.6 ± 14.3, and 77.8 ± 15.616; a Swiss study reported scores of 78 ± 14, 79 ± 14, and 77 ± 1517; and an American study achieved scores of 76.6 ± 20.6, 77.7 ± 20.6, and 75.2 ± 22.6, respectively.18 Nonetheless the Canadian centres were able to achieve a significantly better result in most items and in the summary scores. This might be explained by cross-cultural (different expectations from families), as well as administrative differences (nurse-patient and doctor-patient ratios), but it may also indicate room for further improvement.

Independent factors that affected satisfaction with overall care and identified by this study can be grouped into: care of the patient and family (concern and caring for the patient and family; agitation management), professional care (frequency of communication by nurses; physician skill and competence), and the ICU environment (atmosphere of the ICU and its waiting room). Consistent with prior studies, none of the patient’s or respondent’s characteristics, including the ICU survival status, was found to be independently associated with satisfaction of overall care.16 19 Setting professional skills aside, the perceived physician competence and amount of concern and care shown to patients and their families were largely affected by the communication skill of the health care providers and their manner when interacting with patients and families. The importance of communication has been emphasised by numerous studies.20 21 22 23 24 25 One study found that longer periods of communication between health care providers and families was associated with reduced anxiety among family members of ICU patients.24 They reported a median (range) time of staff contact as 10 (1-60) minutes. In addition to the duration, a proactive, structured, and multidisciplinary communication strategy that incorporated the five objectives in the mnemonic “VALUE” (to Value and appreciate what the family members said, to Acknowledge the family members’ emotions, to Listen, to ask open-ended questions that would allow the caregiver to Understand who the patient was as a person, and to Elicit questions from family members) was shown to lessen symptoms of anxiety, depression, and post-traumatic stress disorder.25 Education and training in communication skills, especially the power of listening and to allow families more opportunity to speak during conferences also improved family satisfaction in the ICU.26 It is also essential to diagnose the root cause of any communication problem.15 Removing barriers in the health care system that discourage communication, for example heavy workload rendering insufficient time spent with families and restrictive visiting policies, would be beneficial.27

Factors in the left upper quadrant of the performance-importance plots (Fig 1) had greater regression weights but performed less satisfactorily, and therefore warrant more urgent attention. Among these were the ICU and waiting room environment. The questionnaire items do not specify the particular areas of concern that individual families had in mind, but responses to the three open-ended questions were illuminating. Comments related to the ICU environment focused on the availability of facilities for patients (visual and audio entertainment devices) and their families (chairs and toilet), ICU noise level, room temperature, space, and privacy. In fact, the ICU environment has been repeatedly identified as a factor that affects satisfaction.13 18 19 One study found that migration of an ICU with multiple beds in one ward to another with single-room design significantly improved family and patient satisfaction.13 These findings offer opportunities for improvement, and also provide valuable information for administrators when designing a new ICU.

Agitation management also warranted more urgent attention (Fig 1a). Although evidence supports maintenance of a light rather than deep level of sedation in adult critically ill patients to shorten duration of mechanical ventilation and ICU length of stay,28 29 a balance needs to be struck to prevent excessive pain, agitation, or adverse experiences that are associated with a higher incidence of post-traumatic stress disorder in ICU survivors and could negatively impact their families.30 The revised 2013 version of Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult ICU Patients has recommended routine monitoring of the depth of sedation and targeted titration of preferably non-benzodiazepine sedatives.31

Our subscore for decision-making was higher than that for overall care, in contrast to the overseas counterparts.16 17 18 We do not know if this is unique to the Chinese population since no other Chinese survey is available for comparison. One interesting finding was that younger respondents were less satisfied with their role in decision-making than older respondents. A similar observation has been made before.32 In this information explosion era where electronic data are easily available, it can be understood that the younger generation wants to play a greater role in making decisions for their sick family member. A paternalistic approach will be less appealing to our future generation, and a deliberative model should therefore be adopted, with an emphasis on provision of complete and honest information to increase their sense of control over the care of their family member.

There are limitations to our study. First, the reason for refusal to participate in the survey was not documented and therefore we cannot rule out a response bias, where dissatisfied families might have declined participation in the survey, thus overestimating satisfaction. The high return rate compared with other studies (76.6% vs 27.8-75.4%15 16 17) would have lessened any effect of a response bias. Second, social desirability bias cannot be ruled out as most respondents completed the questionnaire while their sick family member was still under our care. We tried to minimise this by reassuring families of the confidentiality of their response and providing an envelope in which to return the completed questionnaire that was only opened by researchers at a later time. Third, questionnaires completed before ICU discharge might not reflect the whole ICU experience. Recruiting NOKs when the patient was nearing ICU discharge reduced premature data capture and prevented the otherwise increased administrative cost, increased recall bias, and anticipated lower response rate that would be involved when tracing eligible NOKs following ICU discharge. Fourth, FS-ICU has not been validated in the Chinese language. The Chinese (Taiwan) version provided by CARENET was modified by the co-authors wherein Taiwanese terms were replaced by ones familiar to the Hong Kong people and questions on the respondent’s demographics were added as in the original English questionnaire. This modified version was circulated to and approved by all co-authors to ensure face validity. The high return rate of the questionnaire and the high response rate to questions (95.0%) indicated feasibility of this modified Chinese version.11 Last, this was a single-centre study and thus generalisability of the results to other settings may not be appropriate.

Family satisfaction is an important measure of ICU quality. We found that families were satisfied with the ICU care we provided and with their role in decision-making. Their satisfaction was comparable with most overseas centres. Nonetheless there remains room for improvement when compared with the Canadian database. Future initiatives will focus on improving the ICU environment, agitation management, and enhancing communication with families.

We wish to thank all members of the FAME team including Dr Arthur CW Lau, Ms Nora LP Kwok, Ms L Lau, Ms CH Lee, and Ms HY Wong for their administrative advice and contribution in data collection and entry, and Ms CH Li, Ms WY So, and Ms PS Chiu for subject recruitment. We also wish to thank the Canadian Researchers at the End of Life Network for sharing their FS-ICU database. Current versions of the FS-ICU questionnaire can be found on their website <www.thecarenet.ca/57-researchers/our-projects/family-satisfaction-survey>.

1. Davidson JE, Powers K, Hedayat KM, et al. Clinical practice guidelines for support of the family in the patient-centered intensive care unit: American College of Critical Care Medicine Task Force 2004-2005. Crit Care Med 2007;35:605-22. Crossref

2. Lewin SA, Skea ZC, Entwistle V, Zwarenstein M, Dick J. Interventions for providers to promote a patient-centred approach in clinical consultations. Cochrane Database Syst Rev 2001;(4):CD003267. Crossref

3. Roter DL, Hall JA, Kern DE, Barker LR, Cole KA, Roca RP. Improving physicians’ interviewing skills and reducing patients’ emotional distress. A randomized clinical trial. Arch Intern Med 1995;155:1877-84. Crossref

4. Stewart M, Brown JB, Donner A, et al. The impact of patient-centered care on outcomes. J Fam Pract 2000;49:796-804.

5. Heyland DK, Tranmer JE; Kingston General Hospital ICU Research Working Group. Measuring family satisfaction with care in the intensive care unit: the development of a questionnaire and preliminary results. J Crit Care 2001;16:142-9. Crossref

6. Sundararajan K, Martin M, Rajagopala S, Chapman MJ. Posttraumatic stress disorder in close relatives of intensive care unit patients’ evaluation (PRICE) study. Aust Crit Care 2014;27:183-7. Crossref

7. Schmidt M, Azoulay E. Having a loved one in the ICU: the forgotten family. Curr Opin Crit Care 2012;18:540-7. Crossref

8. Davidson JE, Jones C, Bienvenu J. Family response to critical illness: postintensive care syndrome-family. Crit Care Med 2012;40:618-24. Crossref

9. Flaatten H. The present use of quality indicators in the intensive care unit. Acta Anaesthesiol Scand 2012;56:1078-83. Crossref

10. de Vos M, Graafmans W, Keesman E, Westert G, van der Voort PH. Quality measurement at intensive care units: which indicators should we use? J Crit Care 2007;22:267-74. Crossref

11. Stricker KH, Niemann S, Bugnon S, Wurz J, Rohrer O, Rothen HU. Family satisfaction in the intensive care unit: cross-cultural adaptation of a questionnaire. J Crit Care 2007;22:204-11. Crossref

12. Wall RJ, Engelberg RA, Downey L, Heyland DK, Curtis JR. Refinement, scoring, and validation of the family satisfaction in the intensive care unit (FS-ICU) survey. Crit Care Med 2007;35:271-9. Crossref

13. Jongerden IP, Slooter AJ, Peelen LM, et al. Effect of intensive care environment on family and patient satisfaction: a before-after study. Intensive Care Med 2013;39:1626-34. Crossref

14. Tastan S, Iyigun E, Ayhan H, Kilickaya O, Yilmaz AA, Kurt E. Validity and reliability of Turkish version of family satisfaction in the intensive care unit. Int J Nurs Pract 2014;20:320-6. Crossref

15. Heyland DK, Rocker GM, Dodek PM, et al. Family satisfaction with care in the intensive care unit: results of a multiple center study. Crit Care Med 2002;30:1413-8. Crossref

16. Schwarzkopf D, Behrend S, Skupin H, et al. Family satisfaction in the intensive care unit: a quantitative and qualitative analysis. Intensive Care Med 2013;39:1071-9. Crossref

17. Stricker KH, Kimberger O, Schmidlin K, Zwahlen M, Mohr U, Rothen HU. Family satisfaction in the intensive care unit: what makes the difference? Intensive Care Med 2009;35:2051-9. Crossref

18. Osborn TR, Curtis JR, Nielsen EL, Back AL, Shannon SE, Engelberg RA. Identifying elements of ICU care that families report as important but unsatisfactory: decision-making, control, and ICU atmosphere. Chest 2012;142:1185-92. Crossref

19. Hunziker S, McHugh W, Sarnoff-Lee B, et al. Predictors and correlates of dissatisfaction with intensive care. Crit Care Med 2012;40:1554-61. Crossref

20. Scheunemann LP, McDevitt M, Carson SS, Hanson LC. Randomized, controlled trials of interventions to improve communication in intensive care: a systematic review. Chest 2011;139:543-54. Crossref

21. Kodali S, Stametz RA, Bengier AC, Clarke DN, Layon AJ, Darer JD. Family experience with intensive care unit care: association of self-reported family conferences and family satisfaction. J Crit Care 2014;29:641-4. Crossref

22. Lily CM, De Meo DL, Sonnar LA, et al. An intensive communication intervention for the critically ill. Am J Med 2000;109:469-75. Crossref

23. Shelton W, Moore CD, Socaris S, Gao J, Dowling J. The effect of a family support intervention on family satisfaction, length-of-stay, and cost of care in the intensive care unit. Crit Care Med 2010;38:1315-20. Crossref

24. Rusinova K, Kukal J, Simek J, Cerny V; DEPRESS study working group. Limited family members/staff communication in intensive care units in the Czech and Slovak Republics considerably increases anxiety in patients’ relatives—the DEPRESS study. BMC Psychiatry 2014;14:21. Crossref

25. Lautrette A, Darmon M, Megarbane B, et al. A communication strategy and brochure for relatives of patients dying in the ICU. N Engl J Med 2007;356:469-78. Crossref

26. McDonagh JR, Elliott TB, Engelberg RA, et al. Family satisfaction with family conferences about end-of-life care in the intensive care unit: increased proportion of family speech is associated with increased satisfaction. Crit Care Med 2004;32:1484-8. Crossref

27. Curtis JR, Patrick DL, Shannon SE, Treece PD, Engelberg RA, Rubenfeld GD. The family conference as a focus to improve communication about end-of-life care in the intensive care unit: opportunities for improvement. Crit Care Med 2001;29(2 Suppl):N26-33. Crossref

28. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342:1471-7. Crossref

29. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371:126-34. Crossref

30. Granja C, Gomes E, Amaro A, et al. Understanding posttraumatic stress disorder–related symptoms after critical care: the early illness amnesia hypothesis. Crit Care Med 2008;36:2801-9. Crossref

31. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263-306. Crossref

32. Crow R, Gage H, Hampson S, et al. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature. Health Technol Assess 2002;6:1-244. Crossref

Eczema or atopic dermatitis (AD) is a chronically relapsing dermatosis associated with atopy, and characterised by reduced skin hydration (SH), impaired skin integrity (transepidermal water loss [TEWL]), and poor quality of life as a result of deficient ceramides in the epidermis.1 Regular application of a moisturiser is the key step in its management. Moisturiser therapy for AD is significantly complicated by the diversity of disease manifestations and by a variety of complex immune abnormalities.1 Filaggrin (filament-aggregating protein) and related moisturising factors have an important function in epidermal differentiation and barrier function, and null mutations within the filaggrin gene are major risk factors for developing AD.2 3 4 5 6 Ceramides and related lipid products are also important components in skin barrier function.7 Recent advances in the understanding of the pathophysiological process of AD have led to the production of new moisturisers targeted at correcting the reduced amount of ceramides and natural moisturising factors in the stratum corneum with ceramides, pseudoceramides, or natural moisturising factors.7 Many proprietary products claim to have these ingredients, but have no or limited studies to document their clinical efficacy. Our group previously tested a number of these commercial products and found patient preference and acceptability may influence outcomes of topical treatment independent of the ingredients in these products.8 The purposes of this study were to investigate patient acceptability of a cream/cleanser combination containing lipid complex and shea butter extract with claimed antihistaminergic properties, and evaluate its efficacy in improving the clinical and biophysiological properties of the skin in AD patients. A MEDLINE search was also performed to evaluate whether evidence of efficacy of many of the proprietary moisturisers exists.

Consecutive patients with AD who were interested in trying a new moisturiser were recruited from the paediatric dermatology clinic at a university teaching hospital in Hong Kong. Diagnosis of AD was based on the UK working group criteria.9 In this study, SH and TEWL in the right forearm (2 cm below the antecubital flexure), and disease severity (SCORing Atopic Dermatitis [SCORAD] index) were measured. We have previously described our method of standardising measurements of SH and TEWL.10 After acclimatisation in the consultation room with the patient sitting comfortably in a chair for 20 to 30 minutes, SH (in arbitrary units) and TEWL (in g/m²/h) were then measured according to the manufacturer’s instructions with the Mobile Skin Center MSC 100 equipped with a Corneometer CM 825 (Courage + Khazaka electronic GmbH, Cologne, Germany), and a Tewameter TM 210 probe (Courage + Khazaka electronic GmbH). We documented that a site 2 cm distal to the right antecubital flexure was optimal for standardisation. Oozing and infected areas were avoided by moving the probe slightly sideways.10 The clinical severity of AD was assessed with the SCORAD index.11 12 The SCORAD index also scores pruritus and sleep loss/disturbance on a scale of 0 to 10 (0 being not affected and 10 being most severely affected).

Patients were given a liberal supply of a trial cream containing lipid complex with shea butter extract for eczema (Ezerra [E]; Hoe Pharma, Petaling Jaya, Malaysia) and body wash (E, Hoe Pharma). The moisturiser contained STIMU-TEX AS (Centerchem Inc, Norwalk [CT], US) and saccharide isomerate. The wash contained STIMU-TEX AS and Amisoft (Amisoft Technologies Ltd, Brentwood, UK). The patients were instructed not to use any other moisturiser or topical treatment. Use of any medications such as topical corticosteroid or oral antihistamine was documented. Patients were encouraged to use the test moisturiser at least twice daily on the flexures and areas with eczema. In case the emollient effect was not satisfactory, they could use their usual emollient and medications, but the frequency of such use was to be reported and they must continue with the E moisturiser. The patients were reviewed at the end of 4 weeks. Measurements of SCORAD index, Children’s Dermatology Life Quality Index (CDLQI), SH, and TEWL were repeated. Patients’ global or general acceptability of treatment (GAT) was recorded as ‘very good’, ‘good’, ‘fair’, or ‘poor’.8 13 Approval was obtained from the Clinical Research Ethics Committee of the Chinese University of Hong Kong and written informed consents were obtained from the guardian and patient.

Continuous data were expressed as mean and standard deviation. Mann-Whitney U test was used for intergroup comparison and Wilcoxon signed rank test for within-group comparison as a small number of patients was included. Categorical data were presented in counts. Chi squared test or Fisher’s exact test where appropriate was used to compare intergroup categorical data, while McNemar’s test was used to compare within-group categorical data. Fisher’s exact test was used to determine the GAT of previously used proprietary products and E moisturiser and wash. All comparisons were two-tailed, and P values of <0.05 were considered to be statistically significant. The results were also compared with the data for an emollient (C) containing ceramide-precursor lipids and moisturising factors (n=24).14

Between 1 April 2013 and 31 March 2014, 34 patients (56% boys; mean [± standard deviation] age, 12.1 ± 4.4 years) with AD were recruited and treated with applications of a moisturising cream (E). Compliance was good and patients generally managed to use the moisturiser daily. Among the patients, 74% reported ‘very good’ or ‘good’ acceptability, whereas 26% reported ‘fair’ or ‘poor’ acceptability of the moisturiser (Tables 1 and 2).

There were no intergroup differences in pre-usage clinical parameters of age, objective SCORAD index, pruritus, sleep loss, SH, TEWL, topical corticosteroid usage, oral antihistamine usage, or GAT of prior emollient (Table 2). Following use of the E cream, pruritus score and CDLQI were lower in the ‘very good’/‘good’ group than in the ‘fair’/‘poor’ group. Mean pruritus score decreased from 6.7 to 6.0 (P=0.036) and mean CDLQI improved from 10.0 to 8.0 (P=0.021) in the ‘very good’/‘good’ group (Table 2).

When analysed for the association of the rating of acceptability, the acceptability of E cleanser (P=0.526) and E cream (P=0.537) was not significantly associated with their respective pre-trial products (Table 1). Patients who preferred the trial moisturiser or wash might or might not have come from the group of poor/fair acceptability of their prior emollient or wash, and vice versa. Prior products included emulsifying ointment and various other proprietary products.

When compared historically with another product containing ceramide-precursor lipids (C) that we tested in a previous report,14 the present shea butter extract–containing cream showed similar efficacy and acceptability (Table 3). It appears that ceramide does not confer superiority in terms of acceptability and clinical efficacy.

A MEDLINE search was performed on selected common proprietary moisturisers/emollients for eczema using the following search terms in combinations: “eczema” OR “atopic dermatitis”, AND “emollient” OR “moisturizer” OR “barrier” OR “barrier repair” OR “natural moisturizing factor” OR “ceramide” OR “pseudoceramide”. We selected literature mainly from the past 10 years, but did not exclude commonly referenced and highly cited older articles. We included and described all randomised trials, case series, and bench studies in barrier repair therapy for eczema, with limits activated (Humans, Clinical Trial, Meta-Analysis, Randomized Controlled Trial, English, published in the past 10 years). Editorials, letters, practice guidelines, reviews, and animal studies were excluded. In addition, the bibliographies of the retrieved articles and our own research database were also hand searched. As of 23 April 2014, 18 articles were obtained (Table 413 27 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48). The common proprietary moisturisers were included. The publications generally provided limited evidence of efficacy and biophysical effects (such as SH and TEWL), but virtually no data on patient acceptability and effects on Staphylococcus aureus colonisation.

Atopic dermatitis is a chronically relapsing dermatosis characterised by pruritus, skin dryness, inflammation, secondary bacterial infection by S aureus, and poor quality of life.1 15 16 17 The stratum corneum normally consists of fully differentiated corneocytes surrounded by natural moisturising factor and a lipid-rich matrix containing cholesterol, free fatty acids, and ceramide. In AD, metabolism of lipid and filaggrin protein is abnormal, causing a deficiency of ceramide and natural moisturising factors and impairment of epidermal barrier function that leads to increased TEWL and abnormal skin integrity.1 4 7 18 19 20 21 Moisturisers form the first-line therapy as maintenance and therapeutic management in childhood-onset AD.1 22 23 Hydration of the skin helps to improve dryness, reduce pruritus, and restore disturbed barrier function. Bathing without the use of moisturiser may compromise SH.24 25 26

In this study, we explored clinical efficacy and acceptability of a proprietary moisturiser (E) containing shea butter extract. The cream was acceptable as ‘very good’ or ‘good’ in about three quarters of patients with AD who tried the moisturiser, and ameliorated their pruritus and improved their quality of life.

Compliance or adherence to usage of the moisturising cream was reflected by the GAT and reported frequency of usage (times per day).27 We did not calculate the amount of moisturising cream used because many parents/patients have discarded the tubes or failed to bring them back for weighing in previous trials. Topical steroid usage is also an important confounding factor in this study. We standardise treatment for all our patients by not changing their existing topical steroid (mometasone furoate) and other medications (ie oral antihistamine, topical immunomodulant, and Chinese medicine). In previous studies, we found that documentation of the exact amount of steroid usage (weight or frequency of usage) was difficult for similar reasons as those for moisturisers.28 Most parents are still concerned about topical steroid usage and tend to use the minimal amount of steroid as far as possible.29

Alternative explanations for the modest within-group changes in pruritus and CDLQI (Table 2) include regression to the mean, detection bias, or confounding by co-treatment with topical corticosteroid or usual emollients. Our study did not demonstrate any reduction in clinical severity or S aureus colonisation. When compared historically with another product (C) containing ceramide-precursor lipids that we tested in a previous report,14 although different patients were involved and the E or C products were not received by patients in the same period, the present E cream showed similar efficacy and acceptability with the use of a similar study protocol as the previous study. It appears that specific ceramide-precursor lipids do not confer superiority in terms of acceptability and clinical efficacy.

Regarding intra-group comparisons, the C cream reduced objective SCORAD index (P=0.027) and increased SH (P=0.015), whereas the E cream reduced pruritus and improved CDLQI only in the ‘very good’/‘good’ group (Table 3). Regarding intergroup comparisons, overall there were no significant differences between the pretreatment and post-treatment parameters for the two moisturisers. We note that in the subgroup analysis, pruritus and CDLQI could be the possible contributing factors for the acceptability in the ‘very good’/‘good’ group for the E cream.

Many proprietary emollients/moisturisers are available in the market.7 22 30 31 Despite claims about their efficacy, little evidence has demonstrated the short- or long-term usefulness of many of these proprietary products. Ceramides, pseudoceramides, or filaggrin protein products have been studied and added to commercial moisturisers to mimic natural skin lipids and moisturising factors.32 Anxious parents often consult their physicians for recommendation as to the choice of an ideal or perfect moisturiser for their child with AD. Physicians need to have some evidence-based understanding about these moisturisers in order to address issues raised by the parents. We performed a MEDLINE search and found that only a few of these products have published clinical data (Table 413 27 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48). The majority either do not have patient acceptability or clinical efficacy data in the scientific literature. The efficacy of ceramides and natural moisturiser factors is generally not scientifically documented. Larger-scale, properly conducted randomised controlled trials with recruitment of more study participants may validate subtle differences in clinical efficacy between different emollients. It is likely that there will be similar outcomes in efficacy if the tested emollient is compared with any other traditional emollient such as aqueous cream or Vaseline (Unilever, London, England). Commercial pharmaceutical companies are often unwilling to supply free samples of their product to compare with an inexpensive product, even if more validated and conclusive results may be obtained by increasing the sample size in clinical trials. That is perhaps why there are so few comparative clinical studies in the medical literature.

In a wider context, AD is a complex multifactorial atopic disease. Monotherapy targeting merely at replacement of ceramides, pseudoceramides, or filaggrin degradation products at the epidermis is often suboptimal. In particular, colonisation with S aureus must be adequately treated before emollient treatment can be optimised.17

The major hindrance to the efficacy of a moisturiser is the patient’s perception as to what an ideal moisturiser should be.8 Indeed, it is often not the product, but the patient’s acceptability that determines whether it may be used consistently. Therefore, the physician caring for a patient with AD must educate and guide the parents and the patient to choose the most acceptable formulation to ensure optimal compliance.

This open-label series confirms our previous experience in emollient research. First, patient acceptance of the strengths, types, and formulations of any novel products need to be studied, preferably in randomised controlled trials. Second, holistic efficacy studies of all clinical parameters (namely severity scores, quality-of-life indices, SH, TEWL, S aureus colonisation, and patient acceptance) must be included. Third, as AD is not a simple epidermal skin disease but rather a complex atopic disease, emollient alone is bound to be suboptimal in efficacy.

Well-designed, large-scale, randomised, placebo-controlled trials to document therapeutic effects on disease severity, skin biophysiological parameters, quality of life, and patient acceptability are needed. Patient’s acceptability of a certain product is pivotal for compliance and clinical outcome. Only few of the many proprietary moisturisers for AD have undergone clinical trials to evaluate clinical efficacy and patient acceptability.

Drs KL Hon and TF Leung have performed research on eczema therapeutics, and written about the subject matter of filaggrin, ceramides, and emollients.

We thank Hoe Pharma in Hong Kong for freely supplying the studied materials. The company, however, was not involved in the design or analysis of the research data. The products used in the present study could be examples of other similar products containing shea butter.

1. Leung AK, Hon KL, Robson WL. Atopic dermatitis. Adv Pediatr 2007;54:241-73. Crossref

2. Sandilands A, Terron-Kwiatkowski A, Hull PR, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007;39:650-4. Crossref

3. Sandilands A, Smith FJ, Irvine AD, McLean WH. Filaggrin’s fuller figure: a glimpse into the genetic architecture of atopic dermatitis. J Invest Dermatol 2007;127:1282-4. Crossref

4. Enomoto H, Hirata K, Otsuka K, et al. Filaggrin null mutations are associated with atopic dermatitis and elevated levels of IgE in the Japanese population: a family and case-control study. J Hum Genet 2008;53:615-21. Crossref

5. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002;47:198-208. Crossref

6. Maintz L, Novak N. Getting more and more complex: the pathophysiology of atopic eczema. Eur J Dermatol 2007;17:267-83.

7. Hon KL, Leung AK. Use of ceramides and related products for childhood-onset eczema. Recent Pat Inflamm Allergy Drug Discov 2013;7:12-9. Crossref

8. Hon KL, Wang SS, Pong NH, Leung TF. The ideal moisturizer: a survey of parental expectations and practice in childhood-onset eczema. J Dermatolog Treat 2013;24:7-12. Crossref

9. Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation. Br J Dermatol 1994;131:406-16. Crossref

10. Hon KL, Wong KY, Leung TF, Chow CM, Ng PC. Comparison of skin hydration evaluation sites and correlations among skin hydration, transepidermal water loss, SCORAD index, Nottingham Eczema Severity Score, and quality of life in patients with atopic dermatitis. Am J Clin Dermatol 2008;9:45-50. Crossref

11. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology 1993;186:23-31. Crossref

12. Kunz B, Oranje AP, Labreze L, Stalder JF, Ring J, Taieb A. Clinical validation and guidelines for the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis. Dermatology 1997;195:10-9. Crossref

13. Hon KL, Wang SS, Lau Z, et al. Pseudoceramide for childhood eczema: does it work? Hong Kong Med J 2011;17:132-6.

14. Hon KL, Pong NH, Wang SS, Lee VW, Luk NM, Leung TF. Acceptability and efficacy of an emollient containing ceramide-precursor lipids and moisturizing factors for atopic dermatitis in pediatric patients. Drugs R D 2013;13:37-42. Crossref

15. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113:651-7. Crossref

16. Hon KL, Lam MC, Leung TF, et al. Clinical features associated with nasal Staphylococcus aureus colonisation in Chinese children with moderate-to-severe atopic dermatitis. Ann Acad Med Singapore 2005;34:602-5.

17. Hon KL, Wang SS, Lee KK, Lee VW, Fan LT, Ip M. Combined antibiotic/corticosteroid cream in the empirical treatment of moderate to severe eczema: friend or foe? J Drugs Dermatol 2012;11:861-4.

18. Hanifin JM, Rajka RG. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980;2:44-7.

19. Hanifin JM. Atopic dermatitis. J Am Acad Dermatol 1982;6:1-13. Crossref

20. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 2005;6:328-40. Crossref

21. Leung DY, Nicklas RA, Li JT, et al. Disease management of atopic dermatitis: an updated practice parameter. Joint Task Force on Practice Parameters. Ann Allergy Asthma Immunol 2004;93(3 Suppl 2):S1-21. Crossref

22. Hon KL, Leung AK, Barankin B. Barrier repair therapy in atopic dermatitis: an overview. Am J Clin Dermatol 2013;14:389-99. Crossref

23. Krakowski AC, Eichenfield LF, Dohil MA. Management of atopic dermatitis in the pediatric population. Pediatrics 2008;122:812-24. Crossref

24. Lancaster W. Atopic eczema in infants and children. Community Pract 2009;82:36-7.

25. Tarr A, Iheanacho I. Should we use bath emollients for atopic eczema? BMJ 2009;339:b4273. Crossref

26. Hon KL, Leung TF, Wong Y, So HK, Li AM, Fok TF. A survey of bathing and showering practices in children with atopic eczema. Clin Exp Dermatol 2005;30:351-4. Crossref

27. Hon KL, Ching GK, Leung TF, Choi CY, Lee KK, Ng PC. Estimating emollient usage in patients with eczema. Clin Exp Dermatol 2010;35:22-6. Crossref

28. Hon KL, Leung TF, Ng PC, et al. Efficacy and tolerability of a Chinese herbal medicine concoction for treatment of atopic dermatitis: a randomized, double-blind, placebo-controlled study. Br J Dermatol 2007;157:357-63. Crossref

29. Hon KL, Kam WY, Leung TF, et al. Steroid fears in children with eczema. Acta Paediatr 2006;95:1451-5. Crossref

30. Roos TC, Geuer S, Roos S, Brost H. Recent advances in treatment strategies for atopic dermatitis. Drugs 2004;64:2639-66. Crossref

31. Baumer JH. Atopic eczema in children, NICE. Arch Dis Child Educ Pract Ed 2008;93:93-7.

32. Park KY, Kim DH, Jeong MS, Li K, Seo SJ. Changes of antimicrobial peptides and transepidermal water loss after topical application of tacrolimus and ceramide-dominant emollient in patients with atopic dermatitis. J Korean Med Sci 2010;25:766-71. Crossref

33. Mohammed D, Matts PJ, Hadgraft J, Lane ME. Influence of Aqueous Cream BP on corneocyte size, maturity, skin protease activity, protein content and transepidermal water loss. Br J Dermatol 2011;164:1304-10. Crossref

34. Tsang M, Guy RH. Effect of Aqueous Cream BP on human stratum corneum in vivo. Br J Dermatol 2010;163:954-8. Crossref

35. Simpson E, Böhling A, Bielfeldt S, Bosc C, Kerrouche N. Improvement of skin barrier function in atopic dermatitis patients with a new moisturizer containing a ceramide precursor. J Dermatolog Treat 2013;24:122-5. Crossref

36. Laquieze S, Czernielewski J, Baltas E. Beneficial use of Cetaphil moisturizing cream as part of a daily skin care regimen for individuals with rosacea. J Dermatolog Treat 2007;18:158-62. Crossref

37. Simpson E, Trookman NS, Rizer RL, et al. Safety and tolerability of a body wash and moisturizer when applied to infants and toddlers with a history of atopic dermatitis: results from an open-label study. Pediatr Dermatol 2012;29:590-7. Crossref

38. Miller MA, Borys D, Riggins M, Masneri DC, Levsky ME. Two cases of contact dermatitis resulting from use of body wash as a skin moisturizer. Am J Emerg Med 2008;26:246.e1-2.

39. Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol 2011;10:531-7.

40. Draelos ZD. The effect of ceramide-containing skin care products on eczema resolution duration. Cutis 2008;81:87-91.

41. Madaan A. Epiceram for the treatment of atopic dermatitis. Drugs Today (Barc) 2008;44:751-5. Crossref

42. Palatty PL, Azmidah A, Rao S, et al. Topical application of sandal wood oil and turmeric based cream prevents radiodermatitis in head and neck cancer patients undergoing external beam radiotherapy: a pilot study. Br J Radiol 2014;87:20130490. Crossref

43. Wang S, Kislalioglu MS, Breuer M. The effect of rheological properties of experimental moisturizing creams/lotions on their efficacy and perceptual attributes. Int J Cosmet Sci 1999;21:167-88. Crossref

44. Boffa MJ, Beck MH. Allergic contact dermatitis from quaternium 15 in Oilatum cream. Contact Dermatitis 1996;35:45-6. Crossref

45. Garfield SS. The beneficial effects of oilatum cream on hyperhydrosis. J Am Podiatry Assoc 1966;56:22-4. Crossref

46. Yilmaz E, Borchert HH. Effect of lipid-containing, positively charged nanoemulsions on skin hydration, elasticity and erythema—an in vivo study. Int J Pharm 2006;307:232-8. Crossref

47. Kemeny L, Koreck A, Kis K, et al. Endogenous phospholipid metabolite containing topical product inhibits ultraviolet light–induced inflammation and DNA damage in human skin. Skin Pharmacol Physiol 2007;20:155-61. Crossref

48. Dizon MV, Galzote C, Estanislao R, Mathew N, Sarkar R. Tolerance of baby cleansers in infants: a randomized controlled trial. Indian Pediatr 2010;47:959-63. Crossref