|Year : 2017 | Volume
| Issue : 1 | Page : 1-7
Propranolol for infantile hemangioma: Review of literature
Aditya P Singh, Arvind K Shukla, Pramila Sharma, Aayush Kumar
Department of Pediatric Surgery, SMS Medical College, Jaipur, Rajasthan, India
|Date of Web Publication||16-Aug-2017|
Aditya P Singh
Senior Resident, Near The Mali Hostel, Main Bali Road, Falna, Pali 306116, Rajasthan
Source of Support: None, Conflict of Interest: None
Objective: Hemangioma is the most common benign cutaneous vascular tumor in infants and children. Oral propranolol hydrochloride is a safe and effective medication for treating infantile hemangioma (IH), with decreases in IH volume, color, and elevation. This study reviews propranolol use in IH.
Materials and Methods: We conducted a prospective study of IHs treated with oral propranolol between January 2009 and June 2015. We included 300 children between the ages of 3 months and 5 years with fast-growing IHs in the proliferative phase, ulcerated IHs, and IHs that could cause functional or esthetic problems after the proliferative phase. They received propranolol 2 mg/kg/day, divided 3–4 times daily for 6–12 months and monitored in an outpatient basis. Response to treatment, time of initial, and peak response as well as side effects and sequelae were recorded.
Results: We analyzed 300 IH cases. All the IHs responded to treatment; response was excellent in 45% of the cases, good in 30%, minimal in 15%, and none in 10%. No serious side effects were observed.
Conclusion: In our study, we concluded that oral propranolol is efficacious and safe, with a careful dosing and monitoring regimen for IH.
Keywords: Hemangioma, infantile, propranolol, ulcerated
|How to cite this article:|
Singh AP, Shukla AK, Sharma P, Kumar A. Propranolol for infantile hemangioma: Review of literature. Nigerian J Plast Surg 2017;13:1-7
|How to cite this URL:|
Singh AP, Shukla AK, Sharma P, Kumar A. Propranolol for infantile hemangioma: Review of literature. Nigerian J Plast Surg [serial online] 2017 [cited 2018 Jun 21];13:1-7. Available from: http://www.njps.org/text.asp?2017/13/1/1/213029
| Introduction|| |
The hemangioma incidence in the neonates is 2–3% that increases to 10% in those younger than 1 year of age. These sorts of tumors generally present after the first or second week of birth. Typically, infantile hemangioma (IH) has a rapid proliferating phase, which lasts up to 12 months due to the abundance of α-smooth muscle actin-positive perivascular cells, followed by an involuting phase that lasts 1–5 years, and a regressing period of 5–10 years after the involuting phase.,,,,, In the proliferative phase, vessels’ endothelial cells are immature and disorganized. In involuting phase, however, the number of vessels is reduced and the vessels become mature and enlarged. Finally, connective tissue, fibroblasts, and fat cells replace the vascular tissue.
Complete regression of the lesions is observed in 50 and 90% of the 5- and 9-year-old patients, respectively. A residual fibrofatty mass often persists after the involuting phase. In addition to the complications, the IHs with deep and segmental components might have prolonged growth phase; some of these features include ulceration, disfigurement and scarring, impairment of function, and invasion to vital structures.
Although most hemangiomas are nonproblematic, requiring no treatment, approximately 10% cause significant morbidity predominantly through airway obstruction, ocular compression, functional impairment, or ulceration. Until recently, treatment options for problematic hemangioma have included intralesional and systemic steroids, chemotherapeutic agents including vincristine and interferon-alpha, laser therapy, or surgical intervention.
This case series examines the observed outcomes for children with IH, treated with propranolol, in our institute. A dosing regimen of 1 mg/kg/day is commenced initially, which is increased to 2 mg/kg/day at 1 week if this is well tolerated.
| Materials and methods|| |
All infants brought to our hospital’s pediatric surgery department with hemangioma between January 2009 and June 2015 were studied prospectively. The patients were followed until December 2015. We kept records on the type of hemangioma, phase, location and distribution, size, color, and the presence or not of ulceration or other complications. The main sites of involvement were around the eyes (5%), nose (5%), neck (15%), external genitalia (10%), scalp and head (25%), trunk (15%), extremities (15%), lips (5%), and parotid region (5%). Eighty-five percent of the hemangiomas were focal, and in 66.66%, they were in the proliferative phase [Table 1] and [Table 2]. The treatment was started between the ages of 3 months and 5 years, and the main reason for starting the treatment was rapid growth (60% of the cases) [Table 1]. All 300 patients underwent the workup prior to initiation of therapy. Baseline including full clinical examination (cardiovascular and respiratory), photography, electrocardiogram, echocardiogram, abdominal ultrasound for multiple lesions, and laboratory evaluations including complete blood count, renal function test, blood glucose, serum electrolytes, and thyroid function test were performed. Monitoring of heart rate (HR), blood pressure (BP), and blood glucose was performed at each visit. Improvement was documented objectively by serial photography and observed by us in follow-up clinic for the improvement in size, shape, color, contour, and residual deformity of the lesions.
|Table 1: Assessment of overall effect of propranolol treatment for infantile hemangiomas|
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|Table 2: Meta-analysis about effect of propranolol in infantile hemangioma|
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Participation was offered to children between the ages of 3 months and 5 years with the IHs that had a superficial or deep component or were located in sites that could impair function or result in esthetic disfigurement. Excluded were any patients with the IHs requiring urgent treatment due to impingement on vital structures, patients with contraindications to propranolol, such as wheezing or PHACE (posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/aortic coarctation, and abnormalities of the eye) syndrome (the latter due to a theoretical risk of cerebral ischemia in the presence of an intracerebral vascular anomaly), and those patients with extracutaneous hemangioma that could not be assessed by clinical photography and volume estimation. Majority of the patients were below 6 months (>70%).
| Results|| |
We analyzed 300 IH cases corresponding to 225 girls and 75 boys. Initial response was observed in 65% of the cases. Peak response occurred at 3–4 months. The IH growth stopped by 10 weeks. Significant decrease in the volume of IH with decrease in IH redness and elevation occurred at 8–12 weeks. No significant hypoglycemia, hypotension, or bradycardia occurred. The following factors were predictive of response: focal IH, proliferative phase, periorbital location, and ulceration. The response to treatment was assessed by volume reduction, lightening of color, improvement of symptoms, and parent satisfaction. At each follow-up visit, response to therapy was categorized as excellent, good, minimal, or none by us. The response was excellent in 45% of the cases, good in 30%, minimal in 15%, and none in 10% [Table 1]. We did a meta-analysis of the effect of propranolol in IH with different types, phase, sex, age, and location [Table 2]. All criteria defining each of the four global response categories used by the physicians had to be met. An excellent response was characterized by (a) an estimated reduction of more than 50% of the volume of the hemangioma; (b) 50% clearing of the lesion (color fading); (c) recovery of functional deficit or resolution of bleeding or ulceration; and (d) minimal residual effects (erythema, telangiectasia, or scarring). A good response was characterized by (a) a reduction in the hemangioma volume of 25–50%; (b) 25–50% clearing; (c) recovery of functional deficit or resolution of bleeding or ulceration; and (d) residual effects (either minimal or evident). A minimal response was characterized by (a) a reduction of <25% in the volume of the hemangioma and (b) lack of functional recovery or resolution of bleeding or ulceration. The lack of response to therapy was defined by (a) continued growth of the hemangioma or (b) withdrawal of the drug because of adverse events [Figure 1],[Figure 2],[Figure 3],[Figure 4].
The age at the start of therapy ranged from 3 months to 5 years. Duration of therapy ranged from 6 to 12 months. In 90% of the cases, it was 6 months. No recurrence was observed when the propranolol was discontinued. There were no documented side effects on the dose of 2 mg/kg/day in our study.
| Discussion|| |
Hemangioma is most commonly seen in the head and neck region, with the lesions on the trunk and extremities being less common. In our study, it was 70%. They are more common in Caucasian populations and in female infants. The male-to-female ratio is variable with some reports suggesting that the condition is up to four times more common in females. It was 3:1 in our study. A higher incidence is observed in premature babies and those who were subject to chorionic villous sampling in utero.,
Propranolol is a nonselective beta blocker; in the UK, it is currently licensed for the treatment of arrhythmia, hypertension, Tetralogy of Fallot thyrotoxicosis in children, and migraine prophylaxis. In 2008, regression of a facial hemangioma was noted in a child being treated with propranolol for obstructive hypertrophic myocardiopathy. Since then propranolol has been introduced as a primary treatment for complicated hemangioma. Results from our case series indicate that propranolol at a dose of 2 mg/kg/day is effective in promoting regression and reducing morbidity from problematic cutaneous IHs. Before the introduction of propranolol in 2008, different medications such as systemic corticosteroids and vincristine, with different side effects, were used for years. Over 200 studies concerning propranolol administration have been published.
Previous case series and observational studies have described the rapid onset of propranolol, with the IH color changing from red to purple within 24 h, and softening of the lesions. Most IHs halt growing between 48 h and 1 month.,,,, Our results are not consistent with these findings. These stopped growing after 3 months. The dramatic response of the IHs to propranolol is encouraging and suggests that the early treatment of the IHs could result in decreased scarring and disfigurement.
Propranolol was not completely effective in our study, which differs from other prospective studies in which the efficacy was reported to reach 100%. Other case series have classified children treated with propranolol to be excellent responders (17.2–100%), partial responders (47–60.4%), or nonresponders (1.7–3%).,,,, There was excellent response in 45%, good in 30%, minimal in 15%, and nonresponders in 10% in our study. It may be due to many factors: proliferation phase, age of start of treatment, ulceration, and location. It is unclear why some IHs do not respond as well as others, and whether this is related to factors such as tumor blood supply or expression of β-adrenergic receptors. In certain locations, they may impair vital functions or cause disfigurement (e.g., around the eye, the nasal tip, mouth, and airway). Other complications include bleeding and painful ulceration.
This dose (2 mg/kg/day) has been reported as effective in other centres. We generally advise that propranolol should be given with feeds to reduce the risk of hypoglycemia and to withhold treatment if the child is vomiting or generally unwell.
Prior to treatment, children should undergo some baseline investigations. We have modified our protocol to include the key baseline measurements of pulse, BP, and blood glucose. Children with multiple lesions should have an abdominal ultrasound to exclude hepatic involvement and children with suspected cardiac disease require further investigation with electrocardiogram (ECG), echocardiogram (ECHO), and input from a pediatric cardiologist. Children with segmental and large high-risk facial lesions should have an magnatic resonance imaging (MRI) of the region to delineate local extension. All children should have medical photography prior to the initiation of treatment and regularly throughout treatment to document response to therapy. There were no side effects reported in our study. Lethargy and sleep disturbance are the recognized side effects of propranolol. Well-documented side effects not observed in our group but reported elsewhere include hypoglycaemia gastrointestinal upset and bronchospasm. The children who did not gain benefit from propranolol in our series were those who commenced treatment at an older age. This illustrates the importance of primary care education to ensure that children are identified and treated promptly, ideally within the first 6 months of life.
The effect of propranolol on IH was discovered incidentally, and little is known about its precise mechanism of action in these tumors. Propranolol therapeutic effects are exerted through three mechanisms: vasoconstriction via inhibiting release of nitric oxide;, reduced expression of vascular VEGF, bFGF genes, and metalloproteinase matrix (MMP2/9); and triggering apoptosis of capillary endothelial cells.,,
Propranolol is effective during the proliferative phase of growth. When started at the proliferative stage, the growth of the lesion is inhibited and regression promoted. It may be that the children who did not benefit from the therapy had passed this proliferative stage. Results so far have been promising. Topical 1% propranolol ointment can be effective in treating superficial cutaneous hemangiomas. The treatment was well tolerated without significant side effects, even in patients with numerous or large lesions.
Propranolol is a synthetic, nonselective, β-adrenergic receptor antagonist that lowers the HR and BP. The therapeutic effect of propranolol in hemangioma was explained by Léauté-Labrèze et al. for the first time. Nowadays, propranolol is administered as the first-line treatment for hemangiomas. The advantages of propranolol include its rapid onset of action and good tolerability regardless of sex, age at beginning treatment, type of involvement, ulceration, or depth. Propranolol has been tried to treat the different variants of IH at different locations. It is preferable to administer propranolol as early as possible or before 6 months of age.
Although most of the IHs have an uncomplicated clinical course, approximately 10% of them require treatment because of rapid growth in vital parts, developing local complications such as ulceration, large, or segmental IHs, hemangioma in vital sites (e.g., nose, eyelids, ear, and lips), cosmetic reasons, or functional risks., Hemangiomas may be life threatening when they are present at the upper airways and liver, causing local complications such as hemorrhage, ulceration, and necrosis that lead to septicemia or disseminated intravascular coagulation.
Cardiovascular diseases such as sick sinus syndrome, second- or third-degree atrio-ventricular (AV) block, and asthma are the absolute contraindications for propranolol therapy.,, Infants <3 months of age need inpatient induction for closer monitoring because they are at higher risk for propranolol-induced hypoglycemia; however, home monitoring is possible for older infants.
These guidelines propose a brief inpatient hospitalization (5 days) during therapeutic induction in younger than 2-month-old infants. Propranolol is initiated at a dose of 0.5 mg/kg/day in three divided dosages, and is gradually increased to the desired dose. Despite the development of various protocols, propranolol is usually administered at 1–3 mg/kg/day with many practitioners favoring 2 mg/kg/day;, for ulcerated HOI-hemangioma of infancy (HIS), propranolol doses are 2–3 mg/kg/day.
Treatment duration depends on the type of IH. In deep and mixed IHs, the duration of treatment is longer because the proliferation phase lasts longer; therefore, treatment is continued until 12–16 months of age. In patients with ulceration, treatment is continued up to 9–12 months of age due to the risk of ulceration recurrence. On the other hand, deep periorbital and airway IHs require long-term treatment of up to 15–18 months of age because of potentially life-threatening complications of swelling after cessation of treatment.
Before initiating propranolol therapy, checking baseline vital signs such as HR and BP, finger-stick blood glucose, electrocardiography, and echocardiography are recommended. Hyperkalemia has been reported after early initiation of propranolol therapy and might require treatment with furosemide.
Ahogo et al. reported the relapse risk of 12% in infants who were treated early with oral propranolol for 6 months. Segmental IHs and those with a deep component were mostly at risk of relapse. Females and those with the lesions located on the head and neck area had a higher risk of relapse. Nevertheless, the dosage of oral propranolol did not seem to have any influence on the risk of relapse.The Hemangioma Investigator Group Research Core has developed the following two scales to measure the severity and complications of hemangioma: the Hemangioma Severity Scale (HSS), which measures the overall severity of an IH, and the Hemangioma Dynamic Complication Scale, which assigns severity grades to hemangioma complications. These are to assess the initial status and severity of IH, not to evaluate the response of IH to treatment.
The Hemangioma Activity Score (HAS) is based mainly on the color of the IH, which changes from bright red in the proliferative phase to red/purple/blue and a grayish discoloration in the involution phase. Swelling and ulceration are also assessed. The HAS is used prospectively (on patients) and retrospectively (on photographs). It is objective with only one subjective measurement: estimation of whether the swelling of a deep IH has shrunk by more or less than half. Haggstrom et al. developed another scoring system, the HSS, which measures the overall severity of an IH, using both objective (size, location, risk for associated structural anomalies, and complications) and subjective (pain and risk of disfigurement) items. This system is less valuable when used retrospectively on photographs.
In 2011, the HAS was developed and in 2012, the HSS was described. The developers of the HSS proposed a further system, the Hemangioma Dynamic Complication Scale, which assigns severity grades to IH complications. Because the HAS was not developed for assigning IH severity grades (it merely depicts activity). Obviously, none of these scoring systems can be used for an internal IH. There are two main advantages of the HAS. First, it can be used both prospectively (on patients) and retrospectively (on photographs). The HSS cannot be used retrospectively because information needed for scoring is missing.
The HSS provides a severity score for an individual hemangioma based on the risk stratification of numerous clinical variables, whereas the adjunct hemangioma dynamic complication scale (HDCS) assigns a grade to each complication for longitudinal use.
| Conclusion|| |
Oral propranolol is an effective treatment for IHs for the indications described. Improvement was noted in the majority of our patients’ hemangiomas using the current dosing regimen. No side effects were reported. This contributes to the growing evidence that low dose oral propranolol is a safe, efficacious treatment for problematic hemangiomas. Propranolol hydrochloride administered orally at 2 mg/kg/day reduced the volume, color, and elevation of focal and segmental IH in infants younger than 6 months and children up to 5 years of age.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zimmermann AP, Wiegand S, Werner JA, Eivazi B. Propranolol therapy for infantile haemangiomas: Review of the literature. Int J Ped Otorhinolaryngol 2010;74:338-42.
Zheng JW, Zhang L, Zhou Q, Mai HM, Wang YA, Fan XD et al.
A practical guide to treatment of infantile hemangiomas of the head and neck. Int J Clin Exp Med 2013;6:851-60.
Greenberger S, Bischoff J. Pathogenesis of infantile haemangioma. Br J Dermatol 2013;169:12-9.
Hernandez JA, Chia A, Quah BL, Seah LL. Periocular capillary hemangioma: Management practices in recent years. Clin Ophthalmol 2013;7:1227-32.
Melo JN, Rotter A, Rivitti-Machado MC, Oliveira ZN. Propranolol for treatment of infantile hemangiomas. An Bras Dermatol 2013;88:220-3.
Tu JB, Ma RZ, Dong Q, Jiang F, Hu XY, Li QY et al.
Induction of apoptosis in infantile hemangioma endothelial cells by propranolol. Exp Ther Med 2013;6:574-8.
Sondhi V, Patnaik SK. Propranolol for infantile hemangioma (PINCH): An open-label trial to assess the efficacy of propranolol for treating infantile hemangiomas and for determining the decline in heart rate to predict response to propranolol. J Pediatr Hematol Oncol 2013;35:493-9.
Stiles J, Amaya C, Pham R, Rowntree RK, Lacaze M, Mulne A et al.
Propranolol treatment of infantile hemangioma endothelial cells: A molecular analysis. Exp Ther Med 2012;4:594-604.
Chen TS, Eichenfield LF, Friedlander SF. Infantile hemangiomas: An update on pathogenesis and therapy. Pediatrics 2013;131:99-108.
Mantadakis E, Tsouvala E, Deftereos S, Danielides V, Chatzimichael A. Involution of a large parotid hemangioma with oral propranolol: An illustrative report and review of the literature. Case Rep Pediatr 2012;2012:5.
Luu M, Frieden IJ. Haemangioma: Clinical course, complications and management. Br J Dermatol 2013;169:20-30.
Starkey E, Shahidullah H. Propranolol for infantile haemangiomas: A review. Arch Dis Child 2011;96:890-3.
Leonardi-Bee J, Batta K, O’Brien C, Bath-Hextall FJ. Interventions for infantile haemangiomas (strawberry birthmarks) of the skin. Cochrane Database Syst Rev 2011;11:CD006545.
Schwartz RA, Sidor MI, Musumeci ML, Lin RL, Micali G. Infantile haemangiomas: A challenge in paediatric dermatology. J Eur Acad Dermatol Venereol 2010;24:631-8.
Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: Insights into the molecular mechanisms of action. Br J Dermatol 2010;163:269-75.
The Paediatric Formulary Committee. BNF for Children. BMJ Publishing Group, The Royal Pharmaceutical Society of Great Britain. London: RCPCH Publications Ltd; 2012. p. 89.
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propanolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-51.
Manunza F, Syed S, Laquida B, Linward J, Kennedy H, Gholam K. Propranolol for complicated infantile haemangiomas: A case series of 30 infants. Br J Dermatol 2010;162:466-8.
Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J et al.
Propranolol for severe infantile hemangiomas: Follow-up report. Pediatrics 2009;124:423-31.
Schiestl C, Neuhaus K, Zoller S, Subotic U, Forster-Kuebler I, Michels R et al.
Efficacy and safety of propranolol as firstline treatment for infantile hemangiomas. Eur J Pediatr 2011;170:493-501.
Qin ZP, Liu XJ, Li KL, Zhou Q, Yang XJ, Zheng JW. Treatment of infantile hemangiomas with low-dose propranolol: Evaluation of short-term efficacy and safety. Zhonghua Yi Xue Za Zhi 2009;89:3130-4. [in Chinese].
Buckmiller L, Dyamenhalli U, Richter GT. Propranolol for airway hemangiomas: Case report of novel treatment. Laryngoscope 2009;119:2051-4.
Laforgia N, Milano A, De Leo E, Bonifazi E. Hemangioma and propranolol. Some remarks at the end of treatment. Differences from corticosteroids. Eur J Pediatr Dermatol 2009;19:175-91.
Holmes WJ, Mishra A, Gorst C, Liew SH. Propranolol as first-line treatment for rapidly proliferating infantile haemangiomas. J Plast Reconstr Aesthet Surg 2011;64:445-51.
Love JN, Howell JM, Klein-Schwartz W et al.
Lack of toxicity from paediatric beta blocker exposures. Hum Exp Toxicol 2006;25:341-6.
Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA. Hypoglycaemia in children taking propranolol for the treatment of infantile haemangioma. Arch Dermatol 2010;146:775-8.
Kunzi-Rapp K. Topical propranolol therapy for infantile hemangiomas. Pediatr Dermatol 2012;29:154-9.
Ng SY, Kader Ibrahim SB. A case of PHACES syndrome with successful treatment of facial haemangioma with propranolol. Med J Malaysia 2013;68:364-5.
Al Dosari S, Riad H. Ulcerated nasal infantile haemangioma treated by oral propranolol. Dermatol Online J 2013;19:18298.
de Graaf M, Breur JM, Raphael MF, Vos M, Breugem CC, Pasmans SG. Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants. J Am Acad Dermatol 2011;65:320-7.
Neri I, Balestri R, Patrizi A. Hemangiomas: New insight and medical treatment. Dermatol Ther 2012;25:322-34.
Bagazgoitia L, Torrelo A, Gutierrez JC, Hernandez-Martin A, Luna P, Gutierrez M et al.
Propranolol for infantile hemangiomas. Pediatr Dermatol 2011;28:108-14.
Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: Risks and recommendations. Pediatr Dermatol 2009;26:610-4.
Marqueling AL, Oza V, Frieden IJ, Puttgen KB. Propranolol and infantile hemangiomas four years later: A systematic review. Pediatr Dermatol 2013;30:182-91.
Hong E, Fischer G. Propranolol for recalcitrant ulcerated hemangioma of infancy. Pediatr Dermatol 2012;29:64-7.
Hermans DJ, Bauland CG, Zweegers J, van Beynum IM, van der Vleuten CJ. Propranolol in a case series of 174 patients with complicated infantile haemangioma: Indications, safety and future directions. Br J Dermatol 2013;168:837-43.
Pavlakovic H, Kietz S, Lauerer P, Zutt M, Lakomek M. Hyperkalemia complicating propranolol treatment of an infantile hemangioma. Pediatrics 2010;126:e1589-93.
Ahogo CK, Ezzedine K, Prey S, Colona V, Diallo A, Boralevi F et al.
Factors associated with the relapse of infantile haemangiomas in children treated with oral propranolol. Br J Dermatol 2013;169:1252-6.
Haggstrom AN, Beaumont JL, Lai JS, Adams DM, Drolet BA, Frieden IJ et al.
Measuring the severity of infantile hemangiomas: Instrument development and reliability. Arch Dermatol 2012;148:197-202.
Janmohamed SR, de Waard-van der Spek FB, Madern GC, de Laat PC, Hop WC, Oranje AP. Scoring the proliferative activity of hemangioma of infancy: The Hemangioma Activity Score (HAS). Clin Exp Dermatol 2011;36:715-23.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]