j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Histrelin for central precocious pubertyda single surgeon experience Shannon Rosati, MD,a Rami Maarouf, MD,a Karen Brown, BA,b Michael Poppe, BS,b Dan Parrish, MD,a Jeffrey Haynes, MD,a and David Lanning, MD, PhDa,* a
Virginia Commonwealth University Health System, Division of Pediatric Surgery, Department of General Surgery, Children’s Hospital of Richmond, Richmond, Virginia b Virginia Commonwealth University School of Medicine, Richmond, Virginia
article info
abstract
Article history:
Background: The most common cause of precocious puberty is idiopathic central precocious
Received 2 December 2014
puberty (CPP), which is usually treated with monthly injections. An alternative treatment
Received in revised form
of precious puberty is a subcutaneous implant that contains histrelin acetate, which is
18 March 2015
continuously released for more than 1 y and then removed or replaced with a new implant.
Accepted 25 March 2015
Methods: The aim of this study was to conduct a retrospective review of one surgeon’s
Available online xxx
experience with the histrelin implant and to examine patient satisfaction. After obtaining institutional review board approval, the charts of all children who had undergone at least
Keywords:
one implant were reviewed.
Central precocious puberty
Results: Fifty-eight children, average age 8.4 y old (range 7e14), underwent at least one
Histrelin implant
histrelin implant insertion for treatment of CPP. Parents of 44 patients were able to be reached by telephone for this study and rated the histrelin implant treatment highly. All implants were placed, replaced, or removed without significant difficulty, and there were no complications. Conclusions: This study suggests that the use of a histrelin subcutaneous implant for control of CPP is a safe and effective method for the treatment of this condition. ª 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Precocious puberty is defined as the onset of secondary sexual characteristics before the age of 8 y in girls and 9 y in boys and is associated with an increase in linear growth velocity, acceleration of bone maturation, and can result in early epiphyseal closure if untreated [1e3]. Furthermore, if left untreated, the impact of early maturation because of central precocious puberty (CPP) places children at risk for developing psychological problems, deviant behaviors, and early pregnancy and childbirth when compared with their on-time and late
maturing peers. Children can experience such hostile feelings and marginalization from their peers that psychosocial and behavioral difficulties can be considered as possible reasons to treat [4]. The most common cause of precocious puberty is idiopathic CPP, which occurs much more commonly in girls [5,6]. Goals of therapy involve the restoration of a prepubertal state, and therefore, attenuating the multitude of deleterious effects of early sex steroid exposure on the developing young female or male’s body [6]. CPP has traditionally been treated with monthly injections of depot parenteral preparations of
* Corresponding author. Virginia Commonwealth University Health System, Division of Pediatric Surgery, Department of General Surgery, Children’s Hospital of Richmond, PO Box 980015, Richmond, VA 23298-0015. Tel.: (804) 828-3500; fax: (804) 828-8606. E-mail address: [email protected] (D. Lanning). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.03.071
2
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
gonadotropin-releasing hormone agonists, which was first described in several studies in 1981 [7e9]. One specific preparation first described in 1993, leuprolide acetate for depot injection, has been used for injections to treat CPP in the US [7e15]. An alternative treatment is a subcutaneous implant that contains histrelin acetate, which is continuously released for more than 1 y; it is then removed or replaced with a new implant. Several small studies have described the efficacy of these histrelin implants and the resumption of puberty after its removal [5,6,16,17]. In a recent retrospective, single institution, single surgeon experience with histrelin implant in 114 patients, Davis et al. [18] detailed anticipated complications, most frequently encountered during the removal of implant, including device fracture, impalpability, and migration. Local anesthesia was used in 100% of non-general anesthesia cases. Approximately half of these cases also used conscious sedation, and general anesthesia was only used when patient circumstances and not technical considerations dictated this. Therefore, in line with our institutional experience, conscious sedation was a useful adjunct for the removals or replacement in anticipation of the degree of dissection. However, to our knowledge, no studies to date have examined parent satisfaction with either the implant experience or anesthetic considerations. The aim of this study was to conduct a retrospective review of one surgeon’s experience with the histrelin implant and to examine parent satisfaction in follow-up.
2.
Parents of the patients were contacted by telephone for interviews using contact information from patient charts. Verbal consent was obtained at the start of the phone encounter. The parent or guardian of the patient was then asked a series of questions ranging from the amount of pain to overall satisfaction shown in the Table. These questions included the parents’ overall satisfaction with the operation, the discomfort of the child, type of sedation used, overall satisfaction with the sedation, whether parents would have their child undergo the operation again, the effectiveness of the implant, when the child was able to resume normal activity, whether the child received injections as treatment before implantation, preference of implant versus injection, which was worse in terms of pain and which was better in terms of effectiveness (if applicable), negative aspects of the implant, and satisfaction with the implant overall. The parents’ overall satisfaction, satisfaction with sedation, and satisfaction with the cosmetic appearance were measured on a scale of 1e10, 10 being the best possible outcome. Discomfort from the procedure was measured on a scale of 1e10, with 10 being the most severe. The following questions were assessed using yes or no responses: preference to depot injections, if sedation was required, whether they would undergo the implant, and effectiveness at controlling symptoms of precocious puberty. Negative aspects of the implant were recorded as free responses with parents answering however they saw fit.
Methods 3.
After obtaining approval from institutional review board (#HM20001009), we conducted a retrospective review of one surgeon’s (D.L.) patients with CPP treated with the histrelin implants at the Children’s Hospital of Richmond at Virginia Commonwealth University Medical Center (Richmond, VA) and Bon Secours, St. Mary’s Hospital (Richmond, VA). To place the implants, a local anesthetic cream or patch is applied to the medial aspect of the arm, approximately onethird of the way from the elbow to the axilla, for about 30 min. This site is then cleansed with alcohol before injecting the subcutaneous tissue with about 1 mL of 1% lidocaine with epinephrine. After the area is prepped and draped in standard fashion, a transverse, full-thickness skin incision is made with a scalpel and a subcutaneous pocket is created in a cephalad direction with a small surgical clamp. The implant is then delivered with the delivery device provided in the insertion kit before closing the incision with one interrupted 5-0 absorbable suture. The incision is covered with steri-strips or skin glue. When removing the implant, the skin is prepared in a similar fashion but after the incision is made, the capsule around the end of the implant is gently grasped and delivered through the wound. The capsule is then incised to expose the implant, which is then removed. Occasionally, the capsule will be adherent to the implant and will need to be gently incised with fine scissors or dissected off the implant. Care is taken to prevent rupture of the thin-walled implant. However, ultrasound can assist with identifying any remnant piece if it breaks. Lastly, insertion of a new implant can be performed as mentioned previously immediately after an implant is removed, if desired.
Results
Fifty-eight children, average age 8.4 y old (range 7e14), underwent at least one histrelin implant insertion for treatment of CPP. A total of 170 procedures were performed, 99 implants and 70 removals. Telephone contact was achieved for 44 (76%) of the patients. All 44 children received local analgesia at implantation; 32 also received conscious sedation. Thirty-nine children (89%) had at least one implant replacement. Eight children (18%) received injections before undergoing implant insertion; most parents (88%) preferred the implant to the depot injection. Satisfaction averages are shown in Figure 1 for initial insertion, replacement, and removal of implants. On average, parents’ satisfaction with the insertion of the implant rated 9.5 on a scale of 1e10 with 10 being most satisfied; parents’ satisfaction with replacement and removal of the implant was also rated highly at 9.5 and 9.6, respectively. Satisfaction averages for sedation are shown in Figure 2. Again, satisfaction for sedation during the insertion, replacement, and removal of the implants was rated highly by the patients’ parents as well, with averages of 9.1, 9.0, and 9.1, respectively. The averages for patient discomfort are shown in Figure 3. The patients’ discomfort after initial surgical insertion was rated on average at 2.6 with 10 being the most discomfort (range 1e6). Patient discomfort after replacement and removal was at 2.3 and 2.7, respectively. Almost all the parents (95%) stated that they would agree to have their child undergo surgical implantation again. Almost all parents (98%) found the implants to be effective in controlling their children’s symptoms of precocious puberty and most children (93%) returned to baseline function within 24 h. Parents rated
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
3
Table e Telephone satisfaction survey administered to a parent for each patient. Questions for parents as they relate to the experience of their child with histrelin implant 1. How satisfied are you with the cosmetic appearance of your child’s incisions? Scale of 1e10, 10 being most satisfied 2. Rate your overall satisfaction with the operation, for the following (as applicable): Insertion of implant, replacement of implant, removal of implant. Scale of 1e10, 10 being most satisfied 3. Rate your child’s discomfort with the procedure, for the following (as applicable): Insertion of implant, replacement of implant, removal of implant. Scale of 1e10, 1 being the least discomfort 4. Did your child require sedation for the procedure(s)? (Yes or No) If yes, rate satisfaction with the sedation. Scale of 1e10, 10 being most satisfied 5. Would you have your child undergo the implantation again? (Yes or No) 6. Was the implant effective in controlling your child’s symptoms from early puberty? (Yes or No) 7. Did your child resume normal activity within 8 h after the procedure? 12 h? 24 h? 8. Did your child receive injections before receiving the implant? (Yes or No) If the answer to question 8 is yes: a. Do you prefer histrelin implant or injections, regarding pain? b. Do you prefer histrelin implant or injections, regarding effectiveness? c. Which would you choose for further therapy, implant or injection? 9. What were your perceived “downsides” to histrelin therapy?
the cosmetic appearance of the scar after surgery on average at 9.1 on a scale from 1e10 with 10 being the best rating. There were no surgical complications with the placement, replacement, or removal of the implant other than three implants fractured during removal. However, all parts were retrieved with minimal difficulty with the use of ultrasound on two of the procedures. Thirty-three of the 44 parents (75%) reported no downsides of histrelin therapy. Three parents (7%) considered the fact that a surgical procedure was required to be a downside. Individual parents made the following comments: displeasure that the implant was not dissolvable, association of the implant with weight gain, and less growth than expected occurred after the cessation of therapy. Displeasure related to anesthesia included one parent who reported local soreness and one incident of a child waking during implantation. One person questioned whether there was medication present; the downside was that she could not confirm it was a placebo effect.
4.
Discussion
From the time of the description of CPP and its initial treatment with monthly depot injections, there has been the
Fig. 1 e Parent satisfaction with histrelin implant insertion, replacement, and removal, scale 1e10 (10 best).
development of a histrelin implant, which may be more advantageous in a pediatric population for a variety of reasons. Although effective, monthly injections for children are painful, require multiple trips to the doctor, which can be inconvenient for parents. Although depot leuprolide is effective in suppression of the hypothalamic-pituitarygonadal axis and offers very few technical adverse effects (the most common of which is an abscess), the monthly injections remain painful and this can lead to decreased compliance. Although it is possible to undergo less frequent injections, and therefore theoretically have better compliance, with 3-mo depot leuprolide formulations, comparative studies have found more effective and sustained gonadotropin suppression with monthly injections [19]. From the time of the development of the histrelin implant, several small studies have described its efficacy in children regardless of weight or body size [5,6]. In our experience, the response to the implantation, reinsertion, and removal of the histrelin implant has been overwhelming positive, with most parents describing a process that has minimal to no pain during any portion of the treatment and few to no difficulties with sedation. No difficulties with sedation is encouraging, as most patients and
Fig. 2 e Parent satisfaction with sedation for histrelin implant insertion, replacement, and removal, scale 1e10 (10 best).
4
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article
references
Fig. 3 e Patient discomfort with histrelin implant insertion, replacement, and removal, scale 1e10 (10 worst) as determined by the parent.
parents request sedation, with few children receiving only local anesthetic. We also found very few technical complications; we found that should the implant fracture during the removal process, the use of ultrasound can greatly improve the ability to remove it entirely. We also found that if the implant was in place for >14 mo, the addition of bicarbonate to 1% lidocaine with epinephrine for local injection minimized the discomfort associated with the small amount of extra dissection needed for the removal. Parents had overwhelmingly positive reactions and would have their children undergo all portions of the procedure again. Although only 8 (18%) of our patients had previously undergone monthly depot injections, when compared with the histrelin implant, the 88% of parents again preferred the process of implantation, reinsertion, and removal to monthly injections. In addition, most parents (98%) indicated that they thought the treatment was effective and would have their children undergo the procedure again. As the data from our parent questionnaire were obtained retrospectively instead of prospectively, this is a weakness of our study. However, these data suggest that the use of a histrelin subcutaneous implant for control of CPP provides a safe and effective method that, according to parents is associated with minimal discomfort, allows for a quick return to normal function and is a preferred method of treating CPP when compared with depot injections in our limited subset analysis.
Acknowledgment Author contributions: S.F.R. (primary author) wrote the manuscript, contacted patients, collected and analyzed data, and designed study. R.M. compiled all figures, data analysis, edited, and revised the manuscript. K.B. and M.P. contributed toward data analysis, data collection, and literature review. D.P. and J.H. contributed toward study design, data analysis, revision to the manuscript, and abstract. D.L. (senior author) contributed toward study design, literature review, data analysis, and critical revisions to the manuscript.
[1] Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 1997;99:505. [2] Traggiai C, Stanhope R. Disorders of pubertal development. Best Pract Res Clin Obstet Gynaecol 2003;17:41. [3] Klein KO. Precocious puberty: who has it? Who should be treated? J Clin Endocrinol Metab 1999;84:411. [4] Rosenfield RL. Selection of children with precocious puberty for treatment with gonadotropin releasing hormone analogs. J Pediatr 1994;124:989. [5] Hirsch HJ, Gillis D, Strich D, et al. The histrelin implant: a novel treatment for central precocious puberty. Pediatrics 2005;116:798. [6] Eugester EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrlin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin Endocrinol Metab 2007;92:1697. [7] Crowley WF Jr, Comite F, Vale W, Rivier J, Loriaux DL, Cutler GB Jr. Therapeutic use of pituitary desensitization with a long-acting LHRH agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab 1981;52:370. [8] Comite F, Cutler GB Jr, Rivier J, Vale WW, Loriaux DL, Crowley WF Jr. Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone: a preliminary report. N Engl J Med 1981;305:1546. [9] Mansfield MJ, Beardsworth DE, Loughlin JS, et al. Long-term treatment of central precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone: effects on somatic growth and skeletal maturation. N Engl J Med 1983;309:1286. [10] Boepples PA, Mansfield MJ, Wierman ME, et al. Use of a potent, long-acting agonist of gonadotropin-releasing hormone in the treatment of precocious puberty. Endocr Rev 1986;7:24. [11] Luder AS, Holland FJ, Costigan DC, Jenner MR, Wielgasz G, Fazekas ATA. Intranasal and subcutaneous treatment of central precocious puberty in both sexes with a long-acting analog of luteinizing hormone releasing factor. J Clin Endocrinol Metab 1984;58:966. [12] Styne DM, Harris DA, Egli CA, et al. Treatment of true precocious puberty with a potent luteinizing hormonereleasing hormone agonist: effect on growth, sexual maturation, pelvic sonography, and the hypothalamicpituitary-gonadal axis. J Clin Endocrinol Metab 1986;61:142. [13] Pescovitz OH, Comite F, Hench K, et al. The NIH experience with precocious puberty: diagnostic subgroups and response to short-term luteinizing-hormone analogue therapy. J Pediatr 1986;108:47. [14] Kappy MS, Stuart T, Perelman A. Efficacy of leuprolide therapy in children with central precocious puberty. Am J Dis Child 1988;142:1061. [15] Clemons RD, Kappy MS, Stuart TE, Perelman AH, Hoekstra FT. Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
of children with central precocious puberty. Am J Dis Child 1993;147:653. [16] Fisher MM, Lemay D, Eugster EA. Resumption of puberty in girls and boys following removal of the histrelin implant. J Pediatr 2014;13:1. [17] Gillis D, Karavani G, Hirsch HJ, Strich D. Time to menarche and final height after histrelin implant treatment for central precocious puberty. J Pediatr 2013;163:532.
[18] Davis J, Alkhoury F, Burnweit C. Surgical and anesthetic considerations in histrelin capsule implantation for the treatment of precocious puberty. J Pediatr 2014; 49:801. [19] Badaru A, Wilson DM, Bachrach LK, et al. Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab 2006;91:18.
5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Histrelin for central precocious pubertyda single surgeon experience Shannon Rosati, MD,a Rami Maarouf, MD,a Karen Brown, BA,b Michael Poppe, BS,b Dan Parrish, MD,a Jeffrey Haynes, MD,a and David Lanning, MD, PhDa,* a
Virginia Commonwealth University Health System, Division of Pediatric Surgery, Department of General Surgery, Children’s Hospital of Richmond, Richmond, Virginia b Virginia Commonwealth University School of Medicine, Richmond, Virginia
article info
abstract
Article history:
Background: The most common cause of precocious puberty is idiopathic central precocious
Received 2 December 2014
puberty (CPP), which is usually treated with monthly injections. An alternative treatment
Received in revised form
of precious puberty is a subcutaneous implant that contains histrelin acetate, which is
18 March 2015
continuously released for more than 1 y and then removed or replaced with a new implant.
Accepted 25 March 2015
Methods: The aim of this study was to conduct a retrospective review of one surgeon’s
Available online xxx
experience with the histrelin implant and to examine patient satisfaction. After obtaining institutional review board approval, the charts of all children who had undergone at least
Keywords:
one implant were reviewed.
Central precocious puberty
Results: Fifty-eight children, average age 8.4 y old (range 7e14), underwent at least one
Histrelin implant
histrelin implant insertion for treatment of CPP. Parents of 44 patients were able to be reached by telephone for this study and rated the histrelin implant treatment highly. All implants were placed, replaced, or removed without significant difficulty, and there were no complications. Conclusions: This study suggests that the use of a histrelin subcutaneous implant for control of CPP is a safe and effective method for the treatment of this condition. ª 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Precocious puberty is defined as the onset of secondary sexual characteristics before the age of 8 y in girls and 9 y in boys and is associated with an increase in linear growth velocity, acceleration of bone maturation, and can result in early epiphyseal closure if untreated [1e3]. Furthermore, if left untreated, the impact of early maturation because of central precocious puberty (CPP) places children at risk for developing psychological problems, deviant behaviors, and early pregnancy and childbirth when compared with their on-time and late
maturing peers. Children can experience such hostile feelings and marginalization from their peers that psychosocial and behavioral difficulties can be considered as possible reasons to treat [4]. The most common cause of precocious puberty is idiopathic CPP, which occurs much more commonly in girls [5,6]. Goals of therapy involve the restoration of a prepubertal state, and therefore, attenuating the multitude of deleterious effects of early sex steroid exposure on the developing young female or male’s body [6]. CPP has traditionally been treated with monthly injections of depot parenteral preparations of
* Corresponding author. Virginia Commonwealth University Health System, Division of Pediatric Surgery, Department of General Surgery, Children’s Hospital of Richmond, PO Box 980015, Richmond, VA 23298-0015. Tel.: (804) 828-3500; fax: (804) 828-8606. E-mail address: [email protected] (D. Lanning). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.03.071
2
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
gonadotropin-releasing hormone agonists, which was first described in several studies in 1981 [7e9]. One specific preparation first described in 1993, leuprolide acetate for depot injection, has been used for injections to treat CPP in the US [7e15]. An alternative treatment is a subcutaneous implant that contains histrelin acetate, which is continuously released for more than 1 y; it is then removed or replaced with a new implant. Several small studies have described the efficacy of these histrelin implants and the resumption of puberty after its removal [5,6,16,17]. In a recent retrospective, single institution, single surgeon experience with histrelin implant in 114 patients, Davis et al. [18] detailed anticipated complications, most frequently encountered during the removal of implant, including device fracture, impalpability, and migration. Local anesthesia was used in 100% of non-general anesthesia cases. Approximately half of these cases also used conscious sedation, and general anesthesia was only used when patient circumstances and not technical considerations dictated this. Therefore, in line with our institutional experience, conscious sedation was a useful adjunct for the removals or replacement in anticipation of the degree of dissection. However, to our knowledge, no studies to date have examined parent satisfaction with either the implant experience or anesthetic considerations. The aim of this study was to conduct a retrospective review of one surgeon’s experience with the histrelin implant and to examine parent satisfaction in follow-up.
2.
Parents of the patients were contacted by telephone for interviews using contact information from patient charts. Verbal consent was obtained at the start of the phone encounter. The parent or guardian of the patient was then asked a series of questions ranging from the amount of pain to overall satisfaction shown in the Table. These questions included the parents’ overall satisfaction with the operation, the discomfort of the child, type of sedation used, overall satisfaction with the sedation, whether parents would have their child undergo the operation again, the effectiveness of the implant, when the child was able to resume normal activity, whether the child received injections as treatment before implantation, preference of implant versus injection, which was worse in terms of pain and which was better in terms of effectiveness (if applicable), negative aspects of the implant, and satisfaction with the implant overall. The parents’ overall satisfaction, satisfaction with sedation, and satisfaction with the cosmetic appearance were measured on a scale of 1e10, 10 being the best possible outcome. Discomfort from the procedure was measured on a scale of 1e10, with 10 being the most severe. The following questions were assessed using yes or no responses: preference to depot injections, if sedation was required, whether they would undergo the implant, and effectiveness at controlling symptoms of precocious puberty. Negative aspects of the implant were recorded as free responses with parents answering however they saw fit.
Methods 3.
After obtaining approval from institutional review board (#HM20001009), we conducted a retrospective review of one surgeon’s (D.L.) patients with CPP treated with the histrelin implants at the Children’s Hospital of Richmond at Virginia Commonwealth University Medical Center (Richmond, VA) and Bon Secours, St. Mary’s Hospital (Richmond, VA). To place the implants, a local anesthetic cream or patch is applied to the medial aspect of the arm, approximately onethird of the way from the elbow to the axilla, for about 30 min. This site is then cleansed with alcohol before injecting the subcutaneous tissue with about 1 mL of 1% lidocaine with epinephrine. After the area is prepped and draped in standard fashion, a transverse, full-thickness skin incision is made with a scalpel and a subcutaneous pocket is created in a cephalad direction with a small surgical clamp. The implant is then delivered with the delivery device provided in the insertion kit before closing the incision with one interrupted 5-0 absorbable suture. The incision is covered with steri-strips or skin glue. When removing the implant, the skin is prepared in a similar fashion but after the incision is made, the capsule around the end of the implant is gently grasped and delivered through the wound. The capsule is then incised to expose the implant, which is then removed. Occasionally, the capsule will be adherent to the implant and will need to be gently incised with fine scissors or dissected off the implant. Care is taken to prevent rupture of the thin-walled implant. However, ultrasound can assist with identifying any remnant piece if it breaks. Lastly, insertion of a new implant can be performed as mentioned previously immediately after an implant is removed, if desired.
Results
Fifty-eight children, average age 8.4 y old (range 7e14), underwent at least one histrelin implant insertion for treatment of CPP. A total of 170 procedures were performed, 99 implants and 70 removals. Telephone contact was achieved for 44 (76%) of the patients. All 44 children received local analgesia at implantation; 32 also received conscious sedation. Thirty-nine children (89%) had at least one implant replacement. Eight children (18%) received injections before undergoing implant insertion; most parents (88%) preferred the implant to the depot injection. Satisfaction averages are shown in Figure 1 for initial insertion, replacement, and removal of implants. On average, parents’ satisfaction with the insertion of the implant rated 9.5 on a scale of 1e10 with 10 being most satisfied; parents’ satisfaction with replacement and removal of the implant was also rated highly at 9.5 and 9.6, respectively. Satisfaction averages for sedation are shown in Figure 2. Again, satisfaction for sedation during the insertion, replacement, and removal of the implants was rated highly by the patients’ parents as well, with averages of 9.1, 9.0, and 9.1, respectively. The averages for patient discomfort are shown in Figure 3. The patients’ discomfort after initial surgical insertion was rated on average at 2.6 with 10 being the most discomfort (range 1e6). Patient discomfort after replacement and removal was at 2.3 and 2.7, respectively. Almost all the parents (95%) stated that they would agree to have their child undergo surgical implantation again. Almost all parents (98%) found the implants to be effective in controlling their children’s symptoms of precocious puberty and most children (93%) returned to baseline function within 24 h. Parents rated
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
3
Table e Telephone satisfaction survey administered to a parent for each patient. Questions for parents as they relate to the experience of their child with histrelin implant 1. How satisfied are you with the cosmetic appearance of your child’s incisions? Scale of 1e10, 10 being most satisfied 2. Rate your overall satisfaction with the operation, for the following (as applicable): Insertion of implant, replacement of implant, removal of implant. Scale of 1e10, 10 being most satisfied 3. Rate your child’s discomfort with the procedure, for the following (as applicable): Insertion of implant, replacement of implant, removal of implant. Scale of 1e10, 1 being the least discomfort 4. Did your child require sedation for the procedure(s)? (Yes or No) If yes, rate satisfaction with the sedation. Scale of 1e10, 10 being most satisfied 5. Would you have your child undergo the implantation again? (Yes or No) 6. Was the implant effective in controlling your child’s symptoms from early puberty? (Yes or No) 7. Did your child resume normal activity within 8 h after the procedure? 12 h? 24 h? 8. Did your child receive injections before receiving the implant? (Yes or No) If the answer to question 8 is yes: a. Do you prefer histrelin implant or injections, regarding pain? b. Do you prefer histrelin implant or injections, regarding effectiveness? c. Which would you choose for further therapy, implant or injection? 9. What were your perceived “downsides” to histrelin therapy?
the cosmetic appearance of the scar after surgery on average at 9.1 on a scale from 1e10 with 10 being the best rating. There were no surgical complications with the placement, replacement, or removal of the implant other than three implants fractured during removal. However, all parts were retrieved with minimal difficulty with the use of ultrasound on two of the procedures. Thirty-three of the 44 parents (75%) reported no downsides of histrelin therapy. Three parents (7%) considered the fact that a surgical procedure was required to be a downside. Individual parents made the following comments: displeasure that the implant was not dissolvable, association of the implant with weight gain, and less growth than expected occurred after the cessation of therapy. Displeasure related to anesthesia included one parent who reported local soreness and one incident of a child waking during implantation. One person questioned whether there was medication present; the downside was that she could not confirm it was a placebo effect.
4.
Discussion
From the time of the description of CPP and its initial treatment with monthly depot injections, there has been the
Fig. 1 e Parent satisfaction with histrelin implant insertion, replacement, and removal, scale 1e10 (10 best).
development of a histrelin implant, which may be more advantageous in a pediatric population for a variety of reasons. Although effective, monthly injections for children are painful, require multiple trips to the doctor, which can be inconvenient for parents. Although depot leuprolide is effective in suppression of the hypothalamic-pituitarygonadal axis and offers very few technical adverse effects (the most common of which is an abscess), the monthly injections remain painful and this can lead to decreased compliance. Although it is possible to undergo less frequent injections, and therefore theoretically have better compliance, with 3-mo depot leuprolide formulations, comparative studies have found more effective and sustained gonadotropin suppression with monthly injections [19]. From the time of the development of the histrelin implant, several small studies have described its efficacy in children regardless of weight or body size [5,6]. In our experience, the response to the implantation, reinsertion, and removal of the histrelin implant has been overwhelming positive, with most parents describing a process that has minimal to no pain during any portion of the treatment and few to no difficulties with sedation. No difficulties with sedation is encouraging, as most patients and
Fig. 2 e Parent satisfaction with sedation for histrelin implant insertion, replacement, and removal, scale 1e10 (10 best).
4
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e5
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article
references
Fig. 3 e Patient discomfort with histrelin implant insertion, replacement, and removal, scale 1e10 (10 worst) as determined by the parent.
parents request sedation, with few children receiving only local anesthetic. We also found very few technical complications; we found that should the implant fracture during the removal process, the use of ultrasound can greatly improve the ability to remove it entirely. We also found that if the implant was in place for >14 mo, the addition of bicarbonate to 1% lidocaine with epinephrine for local injection minimized the discomfort associated with the small amount of extra dissection needed for the removal. Parents had overwhelmingly positive reactions and would have their children undergo all portions of the procedure again. Although only 8 (18%) of our patients had previously undergone monthly depot injections, when compared with the histrelin implant, the 88% of parents again preferred the process of implantation, reinsertion, and removal to monthly injections. In addition, most parents (98%) indicated that they thought the treatment was effective and would have their children undergo the procedure again. As the data from our parent questionnaire were obtained retrospectively instead of prospectively, this is a weakness of our study. However, these data suggest that the use of a histrelin subcutaneous implant for control of CPP provides a safe and effective method that, according to parents is associated with minimal discomfort, allows for a quick return to normal function and is a preferred method of treating CPP when compared with depot injections in our limited subset analysis.
Acknowledgment Author contributions: S.F.R. (primary author) wrote the manuscript, contacted patients, collected and analyzed data, and designed study. R.M. compiled all figures, data analysis, edited, and revised the manuscript. K.B. and M.P. contributed toward data analysis, data collection, and literature review. D.P. and J.H. contributed toward study design, data analysis, revision to the manuscript, and abstract. D.L. (senior author) contributed toward study design, literature review, data analysis, and critical revisions to the manuscript.
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