Treatment of extravasation injuries in infants and young children: a scoping review and survey

Notes

Permissions

Chapter 1 Background

Intravenous (i.v.) access for the provision of medication and nutrition is a common, and in many cases essential, procedure used for children and infants in hospitals. Although adverse outcomes resulting from i.v. access are rare, the procedure is not without risk. Extravasation injuries are caused by unintended leakages from i.v. lines in which a fluid deviates from its planned pathway (the vein) into surrounding tissue. Extravasation of fluid can cause pain, inflammation, tendon or nerve damage and predispose to local and invasive infection. Initial treatments aim to reduce pain and prevent or minimise local tissue necrosis and associated functional and cosmetic impairment. Longer term treatment of severe extravasation episodes may require skin grafts and prolonged hospitalisation. The severity of injury and likelihood of long-term damage depends on a number of factors, including the type and amount of fluid extravasated, the injury site, how quickly treatment is administered and the treatment itself. 1

The terms ‘extravasation’ and ‘infiltration’ are often used interchangeably in the literature but are sometimes defined separately, based on the type of fluid being administered. 2 A vesicant is any medication or fluid with the potential for causing blisters, severe tissue injury, or necrosis primarily due to biochemical reactions. Vesicants can vary in type but include many cytotoxic agents (such as chemotherapies). Non-vesicants include fluids such as parenteral nutrition and antibiotics that can cause damage primarily due to the mechanical forces exerted. The distinction between ‘extravasation’ (i.e. leakage of a vesicant) and ‘infiltration’ (i.e. leakage of a non-vesicant) can sometimes cause undue confusion as these two types of event are often indistinguishable externally. 3

Chapter 2 Scoping review of treatments for extravasation injuries

Results

Quantity and quality of research available

Following the removal of duplicates retrieved from the database searches, a total of 3830 records were identified for title and abstract screening, from which 289 records were selected as potentially being of interest. Of those records excluded at the title and abstract phase, 63 were excluded for relating to events which were termed ‘extravasation’ but which did not involve skin or muscle tissue, for example events such as cardiac tamponade or pleural effusion (these studies are listed in Appendix 2). Copies of the full texts of 271 papers were assessed for inclusion in the review. Six papers were identified from other sources: checking references or citation searching of key papers. Figure 1 illustrates the flow of studies through the review process and the number of included studies, by study design. Translators were not available for the nine foreign-language papers published in languages other than French, German or Spanish. Of the 26 group studies included in the scoping review,4,21,31–54 only two were comparative. 16,55

FIGURE 1.

Flow chart showing the number of studies identified and eligible for inclusion.

Primary studies of clinical effectiveness and safety

Comparative studies

Only two comparative studies were identified and included in the review, and both were set in the USA. 16,55 Full details of the studies are presented in Table 1. In 1979, Brown et al. 55 published results for a quasi-randomised study which compared three types of treatment: silver sulfadiazine cream with sterile saline cleansing, povidone-iodine with sterile saline cleansing and sterile saline cleansing alone. The 34 study participants had extravasation injuries resulting in skin loss, and were mostly aged < 1 year. Each of the three treatments was given according to one of two possible protocols, depending on the type of skin loss, classified as either full-thickness loss (24 participants) or partial-thickness loss (10 participants). Participants were allocated treatment according to calendar month. The types of infusate causing injury varied, but they mostly comprised parenteral nutrition, with or without antibiotics. The main outcome reported was the time required for wound healing. The authors reported that there were no significant differences between the three treatment protocols in the rate of healing. Four of the children in the full thickness group died and a further two participants died before receiving treatment.

TABLE 1 - Prospective comparative studies of extravasation treatments

NR, not reported; SD, standard deviation.

Study details	Population characteristics	Injury details	Intervention	Results
Authors Brown et al. 197955	Age Range: 5 days–12 years. 22 were aged < 1 year	Method of delivery Varied, but mostly infusions	All patients had their i.v. therapy stopped, the apparatus removed and the affected area elevated. Patients were then allocated one of the following treatments –	Time for wound healing Silver sulfadiazine: ranged between 3 and 10 weeks in the 11 children with full-thickness loss, and 1–5 weeks in the four children with partial-thickness loss
			For patients with partial-thickness skin loss: Apply silver sulfadiazine cream every 8 hours and cover with semi-permeable dressing. Wash area with sterile saline between applications, or Apply povidone-iodine ointment every 8 hours and cover with semi-permeable dressing. Wash area with sterile saline between applications, or Wash area with sterile saline every 8 hours but keep dry and covered with ‘Sta-Tite’ in the intervals
Design Quasi-randomised study. Treatment allocation changed with the calendar month. The study ran for 6 months. Each of the three treatments was therefore used for 2 full months	Comorbidities Varied range, with respiratory distress syndrome, leukaemia, septicaemia, necrotising enterocolitis and Wilm’s tumour among the most frequent	Types of eligible injury Only children with skin loss: partial (e.g. blistering or discolouration) or full thickness	For patients with full-thickness skin loss: Apply silver sulfadiazine cream every 4 hours. Wash area with sterile saline between applications, cover with ‘Sta-Tite’ in the intervals, or Apply wet-to-dry povidone-iodine solution dressings, covered with ‘Sta-Tite’, every 4 hours, or Apply wet-to-dry saline dressings, covered with Sta-Tite, every 4 hours	Povidone-iodine: ranged between 2 and 6 weeks in the six children with full-thickness loss and 3 weeks in the one child with partial-thickness loss
Setting Children’s hospital in PA, USA	Duration of i.v. NR	Sites Mostly dorsum of foot or the hand. Some injuries on shin, ankle, wrist, scalp, arm and abdomen		Saline: ranged between 4 and 8 weeks in the four children with full-thickness loss and 2 and 3 weeks in the three children with partial-thickness loss
Sample size 34	Mean time to treatment NR	Infusates Varied, but mostly parenteral nutrition (0.5% to 2% amino acids in 10% to 12.5% glucose solution) sometimes with antibiotics		No significant difference in the rate of healing among the three treatment protocols is readily apparent. Nevertheless, primary healing occurred in all patients without the need for skin grafting and without loss of function of the affected part
				Four of the full thickness group died. A further two patients died before receiving treatment
Authors Hanrahan 201316	Age NR (‘paediatric population’)	Injury details NR	Hyaluronidase (n = 37) or no hyaluronidase (n = 76)	AHRQ Common Format harm scores were used as an outcome measure
Design Before-and-after study of the implementation of a guideline for using hyaluronidase. 56 Other outcomes included costs, knowledge, extravasation incident reports, hyaluronidase usage reports	Comorbidities NR			To determine if treatment resulted in less harm, subjects were collapsed into two groups: those receiving hyaluronidase (n = 37) and those who did not (n = 76). Mean harm scores were similar: 5.29 and 5.27, respectively
Setting Children’s hospital in Iowa, USA	Duration of i.v. NR		Most of the no hyaluronidase group were treated before the guideline was implemented and most of the hyaluronidase group were treated post implementation. An increase in the frequency of treatment with hyaluronidase was reported from baseline (9%) to implementation (63%)	No events resulted in permanent harm, severe permanent harm, or deaths (harm score > 6)
Sample size 113	Mean time to treatment Pre implementation: 125 minutes (SD = 75)
	Post implementation: 76 minutes (SD = 38)

The second study was a pre–post study on the implementation and evaluation of a guideline for using hyaluronidase. 16 Although very few population details were reported, the study cohorts appeared quite different from the Brown trial,55 as patients were treated quite quickly (within a few hours of injury). Most of the no-hyaluronidase group were treated before the guideline was implemented and most of the hyaluronidase group were treated post implementation. The mean time to receiving treatment was 125 minutes before guideline implementation and 76 minutes post implementation. Most of the outcomes studied did not relate to the effectiveness or safety of hyaluronidase treatment. The exception was the reporting of Agency for Healthcare Research and Quality (AHRQ) Common Format harm scores. To determine if hyaluronidase treatment resulted in less harm, subjects were collapsed into two groups: those receiving hyaluronidase (n = 37) and those not (n = 76). The mean harm scores were very similar, that is, 5.29 and 5.27, respectively. No events resulted in permanent harm, severe permanent harm or deaths (i.e. a harm score of > 6).

Summary

The comparative study evidence identified was scarce and had important limitations in relation to the aims of this scoping review. The Brown et al. 55 study is an old trial of treatments which are little used in the NHS. It was performed in a population of patients with quite severe wounds, where the extravasation injuries may not have been identified for quite some time. The quasi-randomised design meant that the study results may have been influenced by selection bias. The study was also small and, therefore, underpowered to detect treatment differences. The Hanrahan hyaluronidase guideline study16 was not really designed to evaluate treatment effectiveness. Although it did endeavour to determine if hyaluronidase treatment resulted in less harm than no hyaluronidase treatment, the before-and-after design, lack of population details and lack of details on interventions given to the no hyaluronidase group mean that the study’s ‘harm score’ result should not be regarded as a reliable estimate of hyaluronidase effectiveness.

Non-comparative group studies

Details of the identified non-comparative studies are presented in Tables 2–6. Studies were published over the time period 1975–2016. Most were set in Europe or North America and four studies were set in the UK. 21,31,32,57 Most studies were published as full papers, but the exceptions were two studies that were published as letters. 32,33 The included studies covered conservative management interventions (n = 7),34–40 flush-out methods with or without hyaluronidase (n = 7),4,21,31,32,41,42,57 hyaluronidase injections without flush out (n = 2),45,46 artificial skin treatments (n = 2),33,41 and debridement and/or plastic surgery (n = 7). 21,48–53

Conservative management

Seven case series studies described using a conservative management approach to treatment. 34–40 A minority of patients also went on to receive surgery in one study. 34 Study details are reported in Table 2. Only one study was performed prospectively. 39 Sample sizes ranged from 6 to 19 participants. The studies covered the following interventions: hot compress with topical ointment;37 antibiotic/anti-inflammatory ointment mixture followed by dressing;36 wet dressing and localised massage;35 alcohol based dressing;34 cold compresses and elevation;38 a wound care protocol comprising aqueous gel; a hydrofibre sheet; and a hydrocolloid dressing. 39 The final study used a mixed-management approach utilising puncture points (similar to those made in the Gault21 technique) followed by hydrocolloid dressing before scalpel debridement only of dead tissue (so anaesthesia was not needed). 40 The approach used in this study was decided on the basis of the uncertainty encountered when selecting adequate treatments at an early stage because of difficulties in determining the depth and extent of injuries. The treatment goals were to remove infusates and promote wound healing by inducing autolytic debridement and providing a moist environment.

TABLE 2 - Non-comparative studies of conservative management interventions for extravasation injuries

MPS, mucopolysaccharide polysulphate; NR, not reported.

Study details	Population characteristics	Injury details	Intervention	Results
Authors An and Ning 201537	Age Mean 4 months (range 1–9 months)	Method of delivery NR	Wet-hot compresses by small sterile gauze 3 or 4 times per day, with temperature at 40–45 °C and duration of 20–30 minutes per session. Next, MPS cream was applied topically, followed by tender massage for 3–5 minutes	After a median duration of 3 days’ treatment, all patients had complete fluid absorption and were discharged without adverse outcomes at 3 months
Design Retrospective case series	Comorbidities Respiratory tract infection	Types of injury Swelling, masses
Setting Children’s hospital emergency department, China	Duration of i.v. therapy 2–3 days	Sites All scalp
Sample size Six	Mean time to treatment NR	Infusates Mezlocillin and sulbactam sodium
Authors Moon et al. 201236	Age Mean 20 days (31 weeks’ gestation) [range 14–50 days (28–35 weeks’ gestation)]	Method of delivery NR	Local conservative management was given with healing by secondary intention. An antibiotic and anti-inflammatory ointment mixture was topically applied to the whole region of the wound site, followed by a dressing. This was performed twice a day during the acute phase and once a day during the convalescent phase. Systemic prophylactic antibiotics were also given. The necrotic tissue was removed when it was clearly demarcated. After wound closure, topical oil moisturisation and mild compression were applied	The defects had completely closed 14 to 55 days after injury, the vast majority by wound contraction. Parents were shown photos of the initial defects and the final scar. The degree of the parents’ satisfaction was excellent in nine cases of pinpoint scars and linear scars, good in three cases of depressed or mild contracted linear scars and fair in two cases of round hypertrophic scars
Design Retrospective case series	Comorbidities Prematurity	Types of injury Full-thickness defects
Setting Plastic surgery department, South Korea	Duration of i.v. therapy NR	Sites Hand/wrist (n = 5), ankle/foot (n = 8) and elbow (n = 1)
Sample size 13 (14 injuries)	Mean time to treatment NR	Infusates Total parenteral nutrition
Authors Mu et al. 199935	Age NR (neonates)	Method of delivery NR	Wet dressing and localised massage, followed by rehabilitation programme	It took 18 to 50 days for functional recovery. Five lesions still had cosmetic residuals but none required a skin graft
Design Case series (unclear whether retrospective or prospective)	Comorbidities All had neonatal hypocalcaemia. Premature (n = 4) and perinatal asphyxia (n = 2)	Types of injury Calcinosis cutis
Setting Paediatric department, Taiwan	Duration of i.v. therapy Range 5–11 days	Sites Wrist (n = 4), forearm (n = 4), elbow (n = 3), ankle (n = 3)
Sample size Nine	Mean time to treatment NR	Infusates Calcium gluconate
Authors Nandiolo-Anelone et al. 201434	Age Mean 3.6 days. (range 1–9 days)	Method of delivery NR	Alcohol-based dressing 48 hours to 72 hours (n = 6), pre-surgical pro-inflammatory dressing up to 15 days (n = 6), graft excision (n = 4 primary; n = 4 secondary), including 1 with fasciotomy	Total scores VSS: 53% with scores 0 or 1, 26% with scores 2–4, 13% with score 9, 6% lost to follow-up Two deaths: linked to prematurity (n = 1) and oesophageal atresia (n = 1)
Design Retrospective case series	Comorbidities Maternal and fetal infections (n = 6), fetal distress (n = 4), respiratory distress (n = 4), premature birth (n = 2), denutrition (n = 1) and oesophageal atresia (n = 1)	Types of injury Stage III (n = 6) and IV (n = 9) extravasation injuries
Setting Children’s Hospital, Ivory Coast	Duration of i.v. therapy NR	Sites Upper (n = 9) and lower limbs (n = 6)
Sample size 15	Time to injury treatment Mean 3.93 days, (range 1–9 days)	Infusates Serum 10% glucose and calcium chloride
Authors Sawatzky-Dickson and Bodnaryk 200639	Age 1–40 days (24 to 40 weeks’ gestation)	Method of delivery NR	Wound care protocol developed by the authors. Aqueous gel was applied to coat the area of tissue damage but not the surrounding skin. A hydrofibre sheet was placed over the gel. A thin hydrocolloid dressing covered the area for 7 days (or changed sooner if necessary). Antibiotics were given for wound infections	Wound healing times ranged from 1 to 6 weeks. No wounds showed any signs of infection. One patient died before wound healed. Notes on research design: the number of injuries occurring in a year is small so a randomised controlled trial was not possible
Design Prospective case series	Comorbidities NR	Types of injury Sloughing or necrosis. Stage III or IV injuries
Setting Neonatal intensive care unit, Canada	Duration of i.v. therapy NR	Sites Foot (n = 5), hand (n = 3) and forearm (n = 1)
Sample size Nine	Mean time to treatment NR	Infusates Blood transfusion, sodium bicarbonate, parenteral nutrition and dextrose
Authors Sung and Lee 201640	Age 30–39 weeks’ gestation	Method of delivery NR	Multiple wound punctures (using scalpel blade tip) were made and a hydrocolloid dressing applied. This was changed every 6 hours on the first day and with decreasing frequency thereafter. Debridement performed gradually when devitalised tissue began to be demarcated and autolysed – done with a scalpel and without anaesthesia. Mean duration of treatment was 25 days. After healing, silicone gel was recommended for 3 months to prevent hypertrophic scars	Two of the 12 patients presented with necrotic lesions and nine patients eventually progressed to full-thickness open wounds Wound healing times ranged from 8 to 41 days. There were no secondary infections and minor scarring Parents were ‘satisfied with the final results’ There was one contracture of the wrist Notes on research design: controlled prospective studies necessary to confirm findings
Design Retrospective case series	Comorbidities Nine were preterm	Types of injury Skin discolouration (n = 7), bleb (n = 2), necrosis (n = 2) and swelling (n = 1). Nine eventually progressed to full-thickness open wounds
Setting Plastic surgery department, South Korea	Duration of i.v. therapy NR	Sites Wrist (n = 5), ankle (n = 5), hand (n = 1) and antecubital (n = 1)
Sample size 12	Mean time to treatment Between 1 and 10 hours for all but one patient (52 hours)	Infusates Parenteral nutrition
Authors Wang 200738	Age NR	Method of delivery Injections	Cold compresses and elevation	All wounds healed without necrosis
Design Retrospective case series	Comorbidities NR	Types of injury Swelling (n = 13) and pain (n = 4)
Setting NR, USA	Duration of i.v. therapy NR	Sites Arm (n = 10), hand (n = 3), shoulder (n = 1), ankle (n = 1), foot (n = 1) and groin (n = 1)
Sample size 17	Mean time to treatment NR	Infusates Contrast agent

Five of the studies were of neonates,34–36,39,40 one was of infants (mean age 4 months)37 and one did not report on age. 38 Only two studies reported details relating to the delay between the extravasation event and treatment for the extravasation. 34,40 Both the types of infusate extravasated and the extravasation sites varied widely.

Two studies of milder injuries reported that all injuries healed well and without complications. 37,38 The four studies which covered more severe injuries such as full-thickness defects,36 stage III and IV injuries34,39 and calcinosis cutis35 reported long recovery times (typically between 1 and 8 weeks) and scarring in some patients. The mixed-management approach study reported on different severities of injury caused by parenteral nutrition extravasations in preterm neonates. 40 Wound healing times ranged from 8 to 41 days, with one contracture, no secondary infections and minor scarring. 40 It was also reported that parents were ‘satisfied with the final results’. Although 2 out of the 12 patients presented with necrotic lesions, nine patients eventually progressed to full-thickness open wounds.

Across studies, the outcomes used and result details reported were generally limited, although one study did report total scores on the Vancouver Scar Scale (VSS). 34

Flush-out methods

Seven studies reported using a flush-out technique,4,21,31,32,41,42,57 with sample sizes ranging from 14 to 96 patients. All but one of the studies21 was published after the year 2000. Study details are presented in Table 3. Two studies were prospective case series,32,57 with the remainder being retrospective case series (or having unclear methods). 4,21,31,41–43 Four studies used hyaluronidase before saline flush-out21,31,42,57 and three used saline flush-out alone in all patients,4,32 or nearly all patients. 41 Two studies additionally used liposuction in nearly all patients42 or only in a few patients. 21 Two studies reported on both an early referral group (seen within 24 hours) which received flush-out, and a late referral group which received surgical interventions. 21,41

TABLE 3 - Non-comparative studies of flush-out techniques for extravasation injuries

NR, not reported; TPN, total parenteral nutrition.

Study details	Population characteristics	Injury details	Intervention	Results
Authors Andres et al. 200641 (published in Spanish)	Age Mean 3 years	Method of delivery NR	For cases of < 24 hours, the Gault method with saline (500 cc) was used. In two patients hyaluronidase was used before saline flush-out. Includes eight patients who received artificial skin, see Table 5	Seven of the 10 patients treated by the Gault method avoided necrosis and recovered fully
Design Retrospective case series	Comorbidities One with necrotising enterocolitis, one with hyaline membrane disease, five oncology patients, one severe head trauma and one liver transplant patient	Types of injury Not reported for whole cohort though five patients had established necrosis
Setting Paediatric hospital, Spain	Duration of i.v. therapy NR	Sites Dorsum of hand or foot (n = 14) and forehead (n = 1)
Sample size 15 (includes eight patients who received artificial skin, see Table 5)	Mean time to treatment < 24 hours	Infusates Parenteral nutrition (n = 7), calcium gluconate (n = 4) and doxorubicin (n = 4)
Authors Casanova et al. 200142	Age 20 days (1 day to 6 months) (mean weight 2.5 kg)	Method of delivery NR	Gault procedure with hyaluronidase under general anaesthesia in 11 cases. Mild aspiration with a 2-mm microcannula, following a liposuction technique, was then performed through the micro incisions. Aspiration with a 20-mm syringe or by mild mural aspiration. Procedure repeated several times, rinsing the area with saline after each infiltration of hyaluronidase. Extravasation site protected with an oily dressing. In two cases saline was used instead of hyaluronidase. In one case, only the hyaluronidase flush-out was performed	Eleven patients improved, with no skin involvement in ten cases. In one case a pre-existing blister subsided and healed. Three patients developed skin necrosis, which was treated and healed spontaneously
Design Retrospective case series	Comorbidities Six babies were premature	Types of injury Swelling, discolouration, skin damage, blisters, induration
Setting Plastic surgery department, France	Duration of i.v. therapy NR	Sites Foot/ankle (n = 9), hand/wrist (n = 3), elbow (n = 1) and forehead (n = 1)
Sample size 14	Mean time to treatment 3–12 hours	Infusates Dopamine (n = 9), caffeine (n = 2), beta-blocker (n = 1), calcium (n = 1), calcium and amikacine (n = 1)
Authors Ching 2014;31 Wong 201543	Age Mean 36 months (1 day to 17 years)	Method of delivery NR	A total of 62% of patients received an early saline wash-out using the Gault technique. The technique involved creating multiple skin punctures around the periphery of the injury area with an atraumatic cannula and flushing each puncture with 0.9% sodium chloride. All the wash outs also used hyaluronidase	None of the patients who received the Gault technique developed complications. Of the remainder, there were three cases of associated infection, one case of ischaemic toe with subsequent digit amputation and one case of calcinosis cutis (involving prolonged hospitalisation and readmission for secondary infection)
Design Retrospective case series	Comorbidities Prematurity (40%), gastrointestinal (21%), cardiorespiratory (16%), sepsis (16%) and other (7%)	Types of injury NR
Setting Plastic surgery department, UK	Duration of i.v. therapy NR	Sites Upper limb (65%; 40% on the dorsum of hand), lower limb (25%) and other (10%)
Sample size 69	Mean time to treatment 4 hours (range 0.2–24 hours)	Infusates 32% maintenance fluids (glucose, or sodium or potassium chloride), 23% TPN and 45% others
Authors Gault 199321	Age Mean 10 years (range 0–70 years). The study includes some adults but the mean age (and range) suggests most of the population were children	Method of delivery NR	‘Early referral’ group: of the 44 patients seen within 24 hours, 37 were treated with saline flush-out (500 ml) following prior infiltration with hyaluronidase. One with liposuction alone, and six with both. Prophylactic antibiotics were also used for immunosuppression. Following flush-out, a layer of Jelonet™ (Smith & Nephew, Canada) and betadine-soaked gauze was applied, and limb was elevated for 1 day. ‘Late referral’ group needed extensive reconstructive surgery (see Table 6)	Flush-out group (early referral): no tissue damage (n = 39), minor skin necrosis or delayed healing (n = 5)
Design Retrospective case series	Comorbidities NR	Types of injury NR
Setting Plastic surgery unit, UK	Duration of i.v. therapy NR	Sites Varied greatly but mostly hand/forearm or foot/ankle
Sample size 96 (includes patients needing surgery see Table 6)	Mean time to treatment 44 patients within 24 hours	Infusates Varied greatly but mostly calcium, parenteral nutrition, dextrose, vincristine, daunorubicin or doxorubicin
Authors Ghanem et al. 201557	Age Mean 3.2 years, median 0.2 years (range 1 day–16.7 years)	Method of delivery 89% peripheral lines, 9% central lines and 2% other	Evaluation of a hospital guideline of early referral to plastic surgeons and wash out of high-risk cases. Extravasation injuries were diagnosed in 48 out of 82 cases (i.e. vesicant involved). The rest were classed as infiltration injuries. Twenty-two out of the 48 extravasation injuries required wash-out with hyaluronidase, the remainder were treated conservatively with elevation and analgesia. None of the infiltration injuries required wash-out	Limited outcome data reported. Three patients had tissue necrosis. There was satisfactory healing with no requirement for surgical intervention. Two of these three cases were referred later than 24 hours after the injury
Design Prospective case series (audit)	Comorbidities NR	Types of injury NR
Setting Children’s hospital, UK	Duration of i.v. therapy NR	Sites Varied, but most were the upper limbs (60%) or lower limbs (30%)
Sample size 78 (82 injuries)	Time to injury treatment Mean 8.3 hours	Infusates Varied, though TPN for 46% of the extravasation injury group (n = 48). Antibiotics and sodium chloride caused over half the injuries classed as infiltration. No chemotherapeutic extravasation injuries
Authors Harris et al. 200132,44	Age NR (neonates)	Method of delivery NR	Modification of Gault’s saline flush-out technique: 500 ml of saline, to exit via puncture wounds	No episodes of skin or soft tissue loss were recorded and no reconstructive surgery was required
Design Prospective case series (reported in a letter)	Comorbidities NR	Types of injury NR
Setting Neonatal unit, UK	Duration of i.v. therapy NR	Sites NR
Sample size 56 confirmed injuries from 82 referrals	Time to injury treatment Unclear ‘immediately assessed’	Infusates Parenteral nutrition, inotropes, dextrose, calcium, potassium, and bicarbonate
Authors Kostogloudis et al. 20154	Age Mean age 11.6 days. Four neonates were extremely preterm, nine were very preterm, 14 were late preterm and seven were full term. Gestational age range: 24–42 weeks	Method of delivery Peripheral i.v. infusion	Normal saline flush-out (mean 60 ml, range 10–160 ml), two to six full-thickness incisions made. Dressing (paraffin- and povidone-iodine-soaked gauze) and elevation for 24 hours. Dressing changed daily until healing complete	Wound healing in 1–25 days. All infants responded well to wash-out – clinical findings subsided significantly within 24 hours. Twenty-one neonates showed no signs of soft tissue damage 24 hours after treatment and only minor findings, such as blistering and epidermolysis were still present in seven neonates in the next few days
Design Case series (unclear whether or not prospective)	Comorbidities NR	Types of injury Neonates with stage III and IV extravasation injuries were included in the study
Setting Neonatal intensive care unit, Greece	Duration of i.v. therapy NR	Sites Ankle (n = 22 patients), dorsum of hand (n = 6), dorsum of foot (n = 3) and thigh (n = 3)
Sample size 34	Time to injury treatment Range 10–30 minutes	Infusates Parenteral nutrition (n = 28), dextrose 10% (n = 4) and cephalosporin (n = 2)
				Ischaemic signs recorded in six neonates by day 2, but gradually subsided within 25 days. Incisions healed uneventfully within 7–13 days and with minimal scar formation
				Hypoplasia of the toenails noted in one case at 26 months. One neonate had compartment syndrome – emergency fasciotomies, followed by saline irrigation were performed. All incisions healed uneventfully by secondary intention, resulting in fully functional upper extremities with aesthetically acceptable scar formation

Three studies were in neonates,4,32,42 three studies had populations with mean ages of around 3 years,31,41,57 and in one study the mean age was around 10 years. 21 Where such data were reported, patients were treated within 24 hours of the extravasation event, with the quickest treatment (within 10–30 minutes) seen in a study of preterm neonates with stage III and IV extravasation injuries (Millam criteria were used for staging). 4 Infusate types and the extravasation injury sites varied both within and across studies.

For the three studies of neonates, two reported generally positive results but provided little in terms of result details. 32,42 The study of 34 (mostly) preterm neonates presented more result details, reporting good responses with clinical findings subsiding significantly within 24 hours and wound healing in 1 to 25 days. Twenty-one neonates showed no signs of soft tissue damage 24 hours after treatment and only minor findings, such as blistering and epidermolysis, were still present in seven neonates in the next few days. One child had hypoplasia of the toenails at 26 months. One neonate had compartment syndrome; therefore, emergency fasciotomies, followed by saline irrigation were performed. All incisions healed uneventfully by secondary intention with aesthetically acceptable scar formation. 4 This study also reported that gestational age was not significantly related to the incidence of extravasation injuries (p = 0.87), although it did affect the incidence of skin necrosis after severe extravasation injury (p = 0.009); this was more common in extremely low-birthweight neonates. Similar to most of the neonatal studies, there was a lack of detailed results data for the four studies of older children,21,31,41,43,57 with outcome reporting largely focusing on presence/absence of necrosis.

Other studies of hyaluronidase

Two retrospective studies evaluated hyaluronidase injections without flush out. 45,46 One was a study of extravasations from iodinated contrast material and included both adults and children. 45 For the eight included children, the only treatment-related details presented were that two were treated with hyaluronidase, and brief details were reported for one child whose extravasation had a prolonged course. The other study was of 13 neonates and infants, treated within a median time since injury of around 6 hours. Treatment comprised hyaluronidase injections followed by massage with Hirudoid Cream™ (Mobilat Produktions GmbH, Pfaffenhofen, Germany) around the affected area. 46 Brief results were presented with the authors reporting that symptoms improved and no complications were noted at the 48-hour and 3-month follow-ups.

Another study had a much broader scope: to summarise adverse drug event reporting. 47 In this retrospective hospital database study, extravasation injuries accounted for 10% of the 863 events. The paper reported that infants were ‘treated with hyaluronidase’ for 31 out of the 38 parenteral nutrition extravasations, but no details were reported about whether or not flush-out was also used. Details of the population studied and details on outcome data were also very limited. Study details are presented in Table 4.

TABLE 4 - Non-comparative studies of other (non flush-out) hyaluronidase interventions for extravasation injuries

NR, not reported.

Study details	Population characteristics	Injury details	Intervention	Results
Authors Cochran et al. 200245	Age 3 months to 9 years	Method of delivery Four were manual injection	Two were treated with hyaluronidase	No results data relating to all eight children were presented other than ‘one extravasation had a prolonged course’; brief details were reported for this child
Design Retrospective database study	Comorbidities NR	Types of injury NR
Setting Radiology department, USA	Duration of i.v. therapy NR	Sites NR
Sample size Eight children (study also reported data for adults)	Mean time to treatment NR	Infusates All contrast material
Authors Yan et al. 201446	Age Mean 26 days (range 5–150 days)	Method of delivery NR	Hyaluronidase injections and Hirudoid Cream. A 25-gauge needle was used and a total of 1-ml solution (150 U/ml) of hyaluronidase was divided into five 0.2-ml injections: one in the centre and four along the edge of the extravasation sites. Some cases needed another injection several hours after the first injection (contained five 0.2-ml injections). Hirudoid cream was massaged around the affected area	After the treatment, the symptoms improved, and no complications were noted at the follow-up within 48 hours and 3 months. Negligible loss of functional movements of the fingers, hands, arms, feet, or legs was noticed
Design Retrospective case series	Comorbidities Prematurity (n = 5), pneumonia (n = 4), gastrointestinal disorders (n = 2), malnutrition (n = 1) and neonatal jaundice (n = 1)	Types of injury Swelling in all 13, with erythema (n = 5), blister (n = 3) and necrosis (n = 1)
Setting Neonatal department, China	Duration of i.v. therapy NR	Sites Hand (n = 4), leg (n = 3), forearm (n = 3) wrist, armpit and scalp (all n = 1)		For the calcium chloride-treated patient, a scar developed 2 days after treatment, and calcinosis developed 3 weeks after hospital discharge
Sample size 13	Mean time to treatment Median 6.4 hours for 12 cases. For the calcium chloride-treated patient, the hyaluronidase was given after 14 hours	Infusates Total parenteral nutrition (n = 9), calcium chloride, 10% dextrose, immunoglobin and para-aminomethylbenzoic acid + etamsylate (all n = 1)
Authors Crowther et al. 201147	Age Mean 28 days (range 2–93 days) for the 38 patients with extravasation of parenteral nutrition	Method of delivery Mostly peripheral i.v. lines	‘Treated with hyaluronidase’ for 31 of the 38 parenteral nutrition extravasations. No further details were reported about how hyaluronidase was used	A total of 46% full recovery, remainder were referred to wound care (10%) or did not have a documented outcome (44%)
Design Retrospective hospital database study	Comorbidities NR	Infusates A total of 42% parenteral nutrition, other agents such as dopamine, dextrose, potassium chloride, contrast media, ciprofloxacin and fentanyl each made up ≤ 5% of total
Setting Children’s hospital, USA	Duration of i.v. therapy NR	Types of injury NR
Sample size 90	Time to injury treatment NR	Sites NR	Other treatments included elevation, hot or cold compresses, and analgesic use but these were not consistently documented

Artificial skin treatments

Two studies reported the use of artificial skin. 33,41 One was of 26 preterm neonates with partial- and full-thickness wounds arising from hypertonic solutions. 33 The treatment was Hyalomatrix PA (Anika Therapeutics, Bedford, MA, USA), a tissue reconstruction matrix composed of two layers. Eighteen patients had restoration of dermal quote and a rapid re-epithelialisation process after 21 days. Patients were followed up for up to 14 months; four patients had pathological scars and four had debilitating scar contractures needing secondary surgery. The other study reported on the use of artificial skin with two membranes (silicone and bovine tendon collagen mesh) and debridement and skin grafts in children with necrotic extravasation injuries. 41 All eight patients recovered full functionality with only minor scars; no secondary surgery or amputation was necessary. Study details are presented in Table 5.

TABLE 5 - Non-comparative studies of artificial skin interventions for extravasation injuries

NR, not reported.

Study details	Population characteristics	Injury details	Intervention	Results
Authors Andres et al. 200641 (published in Spanish)	Age Mean 3 years	Method of delivery NR	For cases of < 24 hours, the Gault method with saline (500 cc) was used. In five patients, where necrosis was already established (and in three in which it started after the flush-out), the area was covered with artificial skin consisting of two membranes: one comprised a three-dimensional porous fibrillar mesh of bovine tendon collagen next to chondroitin-6-sulfate. The other was a thin sheet of silicone. Necrotic tissue was debrided and after 2 or 3 weeks a partial skin graft was performed	In total, eight patients needed the artificial skin and skin grafts. All recovered full functionality with only minor scars; no secondary surgery or amputation was necessary
Design Retrospective case series	Comorbidities One with necrotising enterocolitis, one with hyaline membrane disease, five oncology patients, one severe head trauma and one liver transplant patient	Types of injury Not reported for whole cohort although five patients had established necrosis
Setting Paediatric hospital, Spain	Duration of i.v. therapy NR	Sites Dorsum of hand or foot (n = 14) and forehead (n = 1)
Sample size 15 (includes 10 flush-out patients, see Table 3)	Mean time to treatment < 24 hours	Infusates Parenteral nutrition (n = 7), calcium gluconate (n = 4) and doxorubicin (n = 4)
Authors Onesti et al. 201233	Age Mean gestational age 32 weeks (range 28–36 weeks)	Method of delivery NR	Hyalomatrix PA (a dermal substitute composed of two layers): first, topical collagenase was applied, then 72 hours later debridement, followed by application of Hyalomatrix PA. After 1 week the area was cleaned and Hyalomatrix PA applied and kept in place for 7 to 11 days. This procedure was continued for a total of 21 days	Eighteen patients had restoration of dermal quote and a rapid re-epithelialisation process after 21 days. Patients were followed up for up to 14 months. Four had pathological scars, four had debilitating scar contractures needing secondary surgery. There were no wound infections
Design Case series (reported in a letter). Unclear whether or not prospective	Comorbidities Preterm neonates	Types of injury Patients with partial- and full-thickness wounds. Cutaneous eschar (n = 8), ulcers, blisters and erythematous wound margins (n = 18)
Setting Plastic surgery department, Italy	Duration of i.v. therapy Mean 3 days (range 2 days–1 week)	Sites Dorsum of hand (n = 11), dorsum of foot (n = 6), forearm (n = 3), ankle (n = 1), leg (n = 3) and scalp (n = 2)
Sample size 26	Time to injury treatment NR	Infusates Hypertonic solution

Debridement and plastic surgery

Seven studies, which were all retrospective, reported on patients who needed debridement and/or plastic surgery. 21,48–53 Most studies were small (sample sizes ranged from 4 to 51 patients) and all except one50 were published before the year 2000. Study details are presented in Table 6. Three studies reported on outcomes following debridement,48,50,53 three reported on debridement and skin grafts,49,51,52 and one reported different types of reconstructive surgery. 21

TABLE 6 - Non-comparative studies of debridement and plastic surgery interventions for extravasation injuries

NR, not reported.

Study details	Population characteristics	Injury details	Intervention	Results
Authors Falcone et al. 198948	Age Mean gestational age 28.5 weeks (range 26–33 weeks)	Method of delivery NR	Enzymatic debridement	All wounds healed completely with no infections and no functional scar contractions at up to 16 months’ follow-up. No skin grafts were needed
Design Retrospective case series	Comorbidities Preterm, hyaline membrane disease, rule out sepsis, patent ductus arteriosus, necrotising enterocolitis, seizures and bronchopulmonary dysplasia	Types of injury Full-thickness injury
Setting Plastic surgery department, USA	Duration of i.v. therapy NR	Sites Foot (n = 13), hand (n = 2) and scalp (n = 1)
Sample size 15 (16 injuries)	Mean time to treatment NR	Infusates Parenteral nutrition (n = 9), electrolyte solution (n = 3) and unknown (n = 3)	Debridement and topical fibrinolysin/deoxyribonuclease ointment (Elase, Parke-Davis, Morris Plains, NJ, USA) every 8 hours. After 5–7 days, process is repeated until the wound begins to re-epithelialise (3–4 weeks)
Authors Gault 199321	Age Mean 10 years (range 0–70 years). The study includes some adults but the mean age (and range) suggests that most of the population were children	Method of delivery NR	‘Early referral’ group: 44 patients, see Table 3	Late referral: no tissue damage (n = 8 patients), minor skin necrosis or delayed healing (n = 17), scar revision (n = 5), skin graft (n = 6), contractures (n = 6), flap coverage required (n = 6), amputation (n = 3 neonates) and infection (n = 1)
Design Retrospective case series	Comorbidities NR	Types of injury NR
Setting Plastic surgery unit, UK	Duration of i.v. therapy NR	Sites Varied greatly but mostly hand/forearm or foot/ankle
Sample size 96 (includes patients receiving flush-out, see Table 3)	Mean time to treatment 44 patients within 24 hours	Infusates Varied greatly but mostly calcium, parenteral nutrition, dextrose, vincristine, daunorubicin or doxorubicin	‘Late referral’ group: 15 of the 51 patients needed extensive reconstructive surgery
Authors Linder et al. 198349,54	Age From 6 months to 14 years	Method of delivery Some i.v. drip, some push	Surgery – debridement and wound closure: mostly split-thickness skin grafts or delayed primary closure	The mean time for wound closure was 49 days (range 10–85 days). Three patients died before wound closure. At least one patient needed a split thickness skin graft but could be more as results not given separately for children and adults. One child developed sympathetic dystrophy syndrome. Some children developed permanent joint stiffness. Other negative outcomes are mentioned but unclear if they were experienced by the child sample
Design Retrospective case series	Comorbidities Mostly acute myelogenous leukaemia or lymphoma	Types of injury Only patients with extensive injuries, defined as 300 cm2 of tissue loss
Setting Plastic surgery department, USA	Duration of i.v. therapy NR	Sites Upper arm, forearm or hand, foot and leg
Sample size 18 (study also included 22 adults)	Mean time to treatment Range 6–62 days	Infusates Doxorubicin hydrochloride	Sodium hypochlorite dressings
			All patients had at least two operations
Authors Sivrioglu 201450	Age 26 days (range 1 day–3 months)	Method of delivery NR	Injuries were initially flushed with saline and a cold compress applied. Oily dressings were applied and skin necrosis developed within a week. Debridement with the VersajetTM Hydrosurgerical system (Smith & Nephew, London, UK) (a waterjet debriding tool) under general anaesthesia. Oily dressings used after debridement	Wounds healed spontaneously by re-epithelialisation. The mean time of full epithelialisation was 14 days. At 1 year, minimal scar formation was noted with no hypertrophic scars
Design Retrospective case series	Comorbidities NR	Types of injury Skin necrosis
Setting Plastic surgery department, Turkey	Duration of i.v. therapy NR	Sites Hand/wrist (n = 5), foot (n = 3) and scalp (n = 1)
Sample size Nine	Mean time to treatment All within 12 hours	Infusates Calcium gluconate
Authors Upton et al. 197951	Age 5.6 years (range 1 week–11 years)	Method of delivery Varied	Debridement and skin grafts. All patients needed two or more operations	Below elbow amputation (n = 1), contractures (n = 2), extensor loss (n = 2), hair loss (n = 1), loss of motion (n = 1) and reconstruction needed (n = 1)
Design Retrospective case series	Comorbidities Varied, including acute leukaemia, head trauma and gastroenteritis	Types of injury Major injuries with full-thickness tissue loss
Setting Various departments in five US hospitals	Duration of i.v. therapy NR	Sites Hand, scalp, forearm, wrist, foot or ankle
Sample size Seven (study also reported on 24 adults)	Mean time to treatment Range 1–42 days	Infusates Varied including dextrose, potassium chloride, doxorubicin hydrochloride, tetracycline
Authors von Heimburg and Pallua 199852 (published in German)	Age Five infants (no further details other than minimum age 2 weeks)	Method of delivery NR	Debridement, temporary wound coverage by allogeneic donor tissue grafts, and autologous split-skin graft	After 15 days there was full healing (defined as time at which no further wound coverage changes were required) in all five infants
Design Actual design is retrospective comparative study. But extractable data for five infants	Comorbidities NR	Types of injury Late phase, requiring surgical intervention
Setting Germany, specialised clinic for plastic, hand and burns surgery	Duration of i.v. therapy NR	Sites Bridge of foot
Sample size Extractable: five infants (one case report)	Mean time to treatment 19 days (range 2–10 weeks), but these figures include 19 adult cases	Infusates NR
Authors Weiss 197553	Age NR (but premature neonates)	Method of delivery NR	Wet dressings and repeated economical debridement	Wounds healed well in 15 to 40 days. Scars were visible but without discolouration
Design Retrospective case series	Comorbidities Neonatal hypocalcaemia	Types of injury Localised skin necrosis
Setting Department of premature infants, Israel	Duration of i.v. therapy Up to 15 days	Sites All scalp
Sample size Four	Mean time to treatment NR, but lesions developed after needle removal	Infusates Calcium gluconate

Three studies were in neonates and all evaluated debridement techniques. 48,50,53 Two were of skin necrosis wounds caused by calcium gluconate,50,53 one of them being in preterm neonates. 53 The other was in preterm neonates with full-thickness injuries, mostly caused by parenteral nutrition. 48

Two studies were in older children: one in children (mean age 5.6 years) with full-thickness tissue loss arising from different types of infusate,51 and one in children with cancer diagnoses such as acute myelogenous leukaemia or lymphoma who had extensive injuries caused by doxorubicin hydrochloride. 49 In two studies, only limited population details for surgery patients were available. 21,52

As would be expected in studies of more severe injuries, the delay between the extravasation event and (surgical) treatment was longer than in the studies of the interventions previously discussed. However, in one neonatal study of debridement, patients were treated within 12 hours of injury. 50 This was because this study actually used a combination of intervention approaches, rather than just debridement. It used conservative management methods and flush-out before debridement using a waterjet debriding tool. 50

Only basic result details were reported for the debridement studies in neonates. The two calcium gluconate studies reported wound healing in 15 to 40 days,53 and a mean of 14 days for full epithelialisation,50 with minimal scar formation at 1 year. 50 The parenteral nutrition study, which was of enzymatic debridement, reported that all 16 wounds healed completely, with no infections and no functional scar contractions at up to 16 months. 48 A study of five infants receiving debridement and skin grafts reported full healing at 15 days. 52 The study in seven older children (mean age 5.6 years) reported an amputation, two contractures, hair loss and loss of motion. 51 The doxorubicin hydrochloride study of children with extensive injuries reported a mean time for wound closure of 49 days. 49 Other outcomes were reported, but this study also reported on adults and separate results for children were not always available.

Summary

Although many types of extravasation injury treatments have been studied in non-comparative studies, the limitations inherent in these studies makes it very difficult to compare results across treatments. Some results have probably been subject to chance effects or biases because most studies were very small and were retrospective in design: 17 out of the 24 studies had sample sizes of < 20 and only three studies were reported as having a prospective design. Furthermore, there was considerable clinical heterogeneity across study populations in factors such as age, types of infusate, injury severity, location of injury and the time gaps between injury and treatment. Differences in results might be a reflection of variation in one or more of these parameters, rather than differences in treatment effect. Volume of infusate may have been another important factor, though this was very rarely reported. Although data on injury severity grading could have helped with interpreting the importance of these issues, few studies reported such data. Finally, the results sections for most studies were very brief and reported limited data for outcomes which were often related to short-term time points. No studies reported pain as an outcome and few studies quantified outcomes, for example, by using measures of scarring, such as scar scores. Only one study reported on whether or not interventions resulted in adverse effects. 46

Uncertainty exists regarding which treatments may be the most promising, particularly with respect to how to treat earlier stage injuries (i.e. injuries which have not become necrotic). Some of the better evidence (in terms of study size and a prospective design) relates to studies of saline flush-out techniques. Notwithstanding the reporting limitations of the results sections of many studies, these techniques appear to be quite promising treatments. The effect of prior infiltration with hyaluronidase before wash out is unclear though.

Neonates were the most frequently studied population, being evaluated in around half of the non-comparative studies. Neonates have more fragile skin and veins and are less able to communicate the presence of injuries compared with older infants; Sung and Lee40 suggested that the use of flush-out methods in neonates may be too invasive to perform and, therefore, proposed a middle ground between conservative management and flush-out: puncture points and hydrocolloid dressing. However, although 2 out of the 12 (mostly) preterm neonates in this South Korean study presented with necrotic lesions, nine eventually progressed to full-thickness open wounds. Additionally, two group studies have performed flush-out treatments in neonates. 4,32 One of them was prospectively performed in a UK neonatal unit, but it was only published as a letter and so only reported the population as ‘neonates’ along with very basic results. 32 The other was conducted in a Greek neonatal intensive care unit in mostly very preterm or late preterm neonates with quite severe (stage III or IV) extravasation injuries. 4 This study reported impressive results with 21 out of the 34 neonates showing no signs of soft tissue damage 24 hours after treatment, and only minor findings (blistering and epidermolysis) still present in seven neonates in the following few days. These results might therefore suggest that flush-out treatments may be more worthy of further study than the middle ground of puncture (without flush-out) and dressing. However, this is merely a suggestion, as although both the studies were of parenteral nutrition extravasations, they differed in an important way: in the Greek study the neonates were treated within 10–30 minutes of injury compared with between 1 and 10 hours in the South Korean study.

Case report studies

There were 106 case report studies identified,58–163 23 of which detailed more than one participant. 62,64,70,75,79,87,102,104,108–111,121,123,129,147,148,153,157,159–162 In total, 163 individual participants were studied. Study characteristics are summarised in Table 7 with full treatment, intervention and outcome details presented in Appendix 3. The age range of the participants was from newborn to 17 years old, with a mean age of 2.1 years. The majority of the case reports were on neonates or young infants with 93 case reports detailing those < 1 month old and 122 examining those < 1 years old.

TABLE 7 - Basic characteristics of case report studies

EDTA, ethylenediaminetetraacetic acid; NR, not reported.

Study authors and date	Design	Age	Infusate	Intervention
Abraham et al. 201258	Case report	9 years	Chloramphenicol and ampicillin	Fasciotomy
Altan et al. 201359	Case report	23 days	Packed red blood cells	Conservative, nitroglycerin
Altmann et al. 201460	Extractable: case report	2 years	Doxorubicin	Conservative, debridement
Amano et al. 200861	Case report	3 years	Parenteral nutrition	Conservative, antibiotics, silver sulfadiazine, debridement
Amaya 201662	Multiple case reports (four patients)	4–32 weeks old (three preterm)	Parenteral nutrition	Saline wash, fasciotomy, debridement, skin graft
Amhaz et al. 201663	Case report	10 days	Adrenalin	Conservative, antibiotics
Aribit et al. 200064	Multiple case reports (two patients)	6 and 11 months	Parenteral nutrition and intralipid	Antibiotics, drainage
Baker et al. 199165	Case report	7 years	Nafcillin sodium	Antibiotics (n = 1), silver sulfadiazine (n = 2), debridement (n = 1), skin graft (n = 1)
Bassi et al. 200766	Case report	10 months	Contrast agent	Conservative, fasciotomy
Berger et al. 1974162	Multiple case reports (three patients)	2 days to 1 month (two preterm)	Unspecified antibiotic	Debridement, skin graft
Beytut et al. 2014163	Case report	7 years	NR	Honey, debridement, skin graft
Bhosale et al. 201267	Case report	16 years	Blood	Conservative, saline wash
Borman et al. 199868	Case report	4 years	Glucose 10% (n = 1), NR (n = 1)	Saline wash
Boyar et al. 201469	Case report	3 weeks (preterm)	Calcium gluconate	Debridement (n = 2), antibiotics (n = 2)
Broom et al. 201670	Multiple case reports (two patients)	6 months to 1 year	NR	Conservative, topical, oxygenotherapy
Chait et al. 197571	Case report	2 years	Dopamine	Antibiotics, debridement, skin graft
Chen et al. 201072	Case report	4 days (preterm)	NR	Fasciotomy
Chiang et al. 200473	Case report	11 days (preterm)	Calcium gluconate (10%)	Conservative, antibiotics, fasciotomy (n = 2)
Ching et al. 201474	Case report	4 days	Calcium gluconate (10%)	Conservative, antibiotics
Cho et al. 200775	Multiple case reports (five patients)	17 to 50 days	Calcium gluconate	Conservative
Cohan et al. 199076	Case report	12 months	Iopamidol	Conservative
D’Acunto et al. 201577	Case report	2 months (preterm)	Balanced electrolyte solution	Conservative, debridement, skin graft
Davé 199378	Case report	3 years	Undefined fluids (no drugs)	Conservative, debridement, skin graft
Davies et al. 199479	Multiple case reports (two patients)	26 and 11 days (both preterm)	Dopamine	Conservative, nitroglycerin
Denkler et al. 198980	Case report	1 day (preterm – two sites: hand/foot)	Dextrose and 25% normal saline	Conservative
Domizio et al. 200681	Case report	2 days (two sites)	Doxorubicin	Debridement, skin graft
Dunn et al. 198482	Case report	5 months	Dextrose saline	Conservative
Duray et al. 198683	Case report	5 years	Calcium gluconate	Conservative
Eckersall et al. 199684	Case report	3 years	i.v. fluids	Antibiotics, debridement, skin graft
Eroglu et al. 200485	Case report	17 years	Parenteral nutrition (lipid infusate)	Drainage
Garcia-Alverez et al. 199986	Case report	2 weeks (administered over first 3 days of life)	Sodium bicarbonate	Conservative
Gibboney et al. 198687	Multiple case reports (two patients)	17 days and 4 weeks (both preterm)	Dextrose solution (5%), 25% saline and potassium chloride	Conservative, fasciotomy, skin graft
Govind et al. 201488	Case report	27 days (preterm)	Erythromycin	Conservative, saline wash, debridement, skin graft
Grabois et al. 200889	Case report	19 days (preterm)	Phenytoin	Fasciotomy
Handler 199090	Case report	4 years	Calcium gluconate (10%)	Conservative, debridement
Hankin et al. 198491	Case report	17 years	Vincristine	Hyaluronidase
Harb et al. 201092	Case report	1 year (preterm)	Parenteral nutrition	Antibiotics, hyaluronidase
Hasija et al. 201493	Case report	3 years	Dextrose solution	Conservative, hyaluronidase
Hey et al. 200594	Case report	12 months	Sodium bicarbonate	Conservative, hyaluronidase
Hironaja et al. 198295	Case report	6 days	Parenteral nutrition (lipids) plus antibiotics	Conservative, hydrogel
Hirsch et al. 201696	Case report	4 days (preterm)	Anthracycline (idarubicin)	DMSO
Hooke 200597	Case report	Adolescent	Antibiotics, NR	Silver sulfadiazine, honey, hydrogel, hyaluronidase
Kameo et al. 201598	Case report	2 years	NR	Conservative
Khan et al. 201499	Case report	29 days (preterm)	Calcium gluconate	Conservative, antibiotics, oxygenotherapy, debridement
Kishi et al. 2014100	Case report	17 years	Intralipid and parenteral nutrition	Conservative
Kuensting 2010101	Case report	6 days	Calcium gluconate	Conservative
Kumar et al. 2001102	Multiple case reports (six patients)	Neonate (preterm) to 2 years	Propofol and lidocaine	Saline wash, debridement, skin graft
Lee et al. 2013103	Case report	1 month (preterm)	Sodium bicarbonate (NaHCO3)	ACTICOAT™ (Smith & Nephew, London, UK)
Lehr et al. 2004104	Multiple case reports (three patients)	4 to 24 days (two preterm)	Arginine	Conservative, debridement, skin graft
Leung et al. 1980105	Case report	6.5 years	Phenobarbital	Antibiotics, debridement, skin graft
Llinares et al. 2005106	Case report	4 years	NR	Ultrasound, hydrogel, debridement
Martin et al. 1994107	Case report	4 months	Phenytoin	NR
Meszes et al. 2017108	Multiple case reports (six patients)	Neonates (range 1–23 days)	NR	Antibiotics, debridement
Mohr et al. 2014109	Multiple case reports (two patients)	3 weeks (preterm), 19 days (preterm)	Parenteral nutrition (dextrose, calcium, potassium, etc)	Saline wash, hyaluronidase
Morrison et al. 1999110	Multiple case reports (four patients)	Neonates (preterm)	Dopamine	Phentolamine
Mukherjee et al. 1977111	Multiple case reports (four patients)	5 years and NR	Phenytoin (diazepam before)	Conservative, hydrocortisone
Nissim et al. 2008112	Case report	1 day	Calcium gluconate	None
Onesti et al. 2012113	Case report	2 days (preterm)	Calcium gluconate	Antibiotics
O’Reilly et al. 1988114	Case report	Neonate	Ceftriaxone sodium	Conservative, fasciotomy
Ozcan et al. 2015115	Case report	14 years	Mannitol	Fasciotomy
Pantelides et al. 2013116	Case report	1 day (preterm)	Dextrose	Conservative, drainage, antibiotics
Park et al. 2015117	Case report	7 months	Two NR, one hydration	Conservative (n = 1) and fasciotomy (n = 2)
Phillips et al. 2009118	Case report	3 months	Calcium gluconate	Antibiotics, debridement
Raffaella et al. 2009119	Case report (two extravasations)	5 years	Calcium solution	Other surgery
Ravenel 1983120	Case report	6 days	Dextrose	Conservative, hyaluronidase
Reilly et al. 1977121	Multiple case reports (three patients)	13, 15 and 17 years	Calcium solution	Conservative, antibiotics
Reynolds 2007122	Case report	2 days (preterm)	Dopamine	Conservative (n = 1) and nitroglycerin (n = 1)
Roberts 1977123	Multiple case reports (five patients)	Neonates (range 1 day–1 year)	Calcium gluconate	Conservative
Rosales et al. 2004124	Case report	75 days (preterm)	Dopamine and tromethamine	Debridement, skin graft and other surgery (n = 1)
Roth et al. 2006125	Case report	31 days	Nafcillin sodium	Conservative (n = 1), hyaluronidase (n = 2) and skin graft (n = 1)
Rustogi et al. 2005126	Case report	4 days (preterm)	Flucloxacillin, calcium gluconate, human immunoglobulin, sodium bicarbonate, dextrose solution and 20% lipid nutrition	Conservative, debridement (n = 3), skin graft
Salameh et al. 2004127	Case report	3.5 years	Fatty acid, lipid and amino acid infusion (n = 4), glucose (n = 1) and dobutamine (n = 1)	Conservative (n = 3), hydrogel (n = 2), debridement (n = 1) and none (n = 1)
Samiee-Zafarghandy et al. 2014128	Case report	1 day (preterm)	Adriamycin	Conservative (n = 1), antibiotics (n = 1) and hydrocortisone (n = 1)
Sanpera et al. 1994129	Multiple case reports (two patients)	3 days and neonate (preterm)	Dextrose (10%) or calcium solutions	Debridement, skin graft (n = 4)
Santoshi et al. 2008130	Case report	Neonate (preterm) (seen at 5 years)	Fluids or electrolyte solution (n = 5; 1 plus erythromycin) and phenytoin (n = 1)	Saline wash, debridement, skin graft (n = 2)
Schäfer et al. 2005131	Case report	2 weeks	Parenteral nutrition (sixth case blood transfusion)	Antibiotics, debridement (n = 2)
Schie et al. 2013132	Case report	33 weeks (preterm)	Calcium gluconate	Antibiotic corticosteroid
Schumacher et al. 1987133	Case report	7 years	Azithomycin	Conservative, antibiotics
Sharief et al. 1994134	Case report (two extravasations)	1 day (and 3 days)	8.4% bicarbonate 20 ml, 10% calcium gluconate 10 ml, 50% glucose 5 ml, 1 : 1000 adrenaline 3 ml and 4.5% human albumin solution 50 ml	Saline wash, liposuction, hyaluronidase
Shenaq et al. 1996135	Case report	10 years	Parenteral nutrition	Topical
Sindal et al. 2015136	Case report	Neonate (preterm)	Dextrose solution (12.5%)	Conservative
Siu et al. 2007137	Case report	2 days (preterm)	Calcium gluconate	Antibiotics
Siwy et al. 1987138	Case report	2 days	Dopamine	Phentolamine
Sokol et al. 1998139	Case report	14 months (preterm)	Arginine and 10% glucose	Conservative
Sonohata et al. 2006141	Case report	14 years	Arginine monohydrochloride (10% in sodium chloride)	Conservative, silver sulfadiazine
Sonohata et al. 2008140	Case report	3 days	6 cc arginine monohydrochloride, 50% diluted in 12 cc of sodium chloride 0.9%	Conservative, topical, Debridement
Soon et al. 2001142	Case report	38 weeks	NR	Honey
Spenny et al. 2004144	Case report	3 years	Oncovin dauno rubicin	Conservative
Stahl et al. 2000143	Case report	10 years	Parenteral nutrition	Saline wash, hyaluronidase
Subedi et al. 2011145	Case report	16 years	Mannitol (20%)	Fasciotomy
Subhani et al. 2001146	Case report	1 day	Doxorubicin	Conservative, DMSO, debridement, skin graft
Talbot et al. 2011147	Multiple case reports (three patients)	7 to 10 months	Hydroxyzine	Conservative, silver sulfadiazine
Tilden et al. 1980148	Multiple case reports (four patients)	15 days to 4 months	Contrast medium (sodium iothalamate 54%)	Antibiotics, debridement, skin graft
Tiras et al. 2005149	Case report	2 days	Calcium gluconate	Skin graft
Tobin 2007150	Case report	1 day (preterm)	Blood, fluids and antibiotics	Other surgery
Tuncer et al. 2006151	Case report	6 years	Phenytoin	Hyaluronidase
Vanwijck and Lengele 1994152	Case Report	9 years	Parenteral nutrition	Conservative, antibiotics
von Muhlendahl 2012153	Multiple case reports (six patients)	14 days (preterm) to 14 months	Arginine monohydrochloride (10%)	Conservative, silver sulfadiazine, debridement, skin graft
Wada et al. 2003154	Case report	Neonate	Dextrose solution; NR (rehydration)	Debridement, skin graft
Wiegand et al. 2010155	Case report	17 years	Parenteral nutrition	Conservative, silver sulfadiazine, debridement, artificial skin
Wolfe et al. 1983156	Case report	2 days	Dopamine	Conservative, topical, antibiotics, debridement
Wong et al. 1992157	Multiple case reports (two patients)	4 and 15 days (both preterm)	Calcium solution and NR	Debridement
Wong et al. 2015158	Case report	4 days	Calcium disodium edetate (EDTA)	Conservative
Yamamoto et al. 1994159	Multiple case reports (two patients)	1 and 4 years	Adriamycin (doxorubicin)	Debridement, skin graft
Yosowitz et al. 1975160	Multiple case reports (seven patients)	2 days to 10 years (two preterm)	Meglumine ioxitalamate	Conservative, antibiotics, saline wash, drainage
Zenk et al. 1981161	Multiple case reports (three patients)	3 days to 4 months	Calcium solution	Conservative, debridement, skin graft

The range of extravasated fluids examined was varied. The majority of individual case reports examined calcium gluconate, amounting to 19% (n = 31) of the total. Parenteral nutrition and dextrose solutions made up the next highest frequency at 12% (n = 19) and 9% (n = 15), respectively. Other extravasated fluids examined were dopamine at 5% (n = 8), nafcillin sodium at 4% (n = 7), phenytoin at 4% (n = 6), arginine at 2% (n = 4), sodium bicarbonate at 2% (n = 4) and doxorubicin at 2% (n = 3). The extravasated material was not reported in 8% of case reports (n = 13).

The extent and quality of reporting of extravasation treatments varied across the studies. The majority of the studies (n = 56) reported the use of conservative management at least initially. 58,59,61,63,65,66,71–74,76–78,80,82,84,86,89–92,94–97,100–104,108,112,113,115,116,118,119,121–123,127,128,133,141,144,145,147,150,152,154–158,161,163 Only 17 of these studies, however, reported using conservative management in isolation for any case report. 58,71,74,76,82,84,86,89,112,116,121–123,133,147,157,158 Topical treatments were reported in 14 studies,61,62,65,69,96,97,100,104,106,108,109,113,132,148 including seven examining silver sulfadiazine,61,65,96,100,109,113,148 two using DMSO,97,106 three using medical honey62,69,109 and four reporting on hydrogel. 104,108,109,132 Hyaluronidase was used in 11 studies79,98,99,101,103,107,109,137,139,155,161 and saline wash out in 10 studies. 63,64,79,92,109,117,125,137,152,153

Surgical techniques were required in at least one participant in 49 of the studies,59,60,62,65–68,70,72,75,77,78,83,85,87,90–93,95–97,102,105,108,110,111,113,117–119,125,127,129,131,132,135,136,143,144,147–149,153,154,159–162 a significant proportion at 46%. Of these, 11 studies included fasciotomies,59,68,70,72,85,90,93,117,143,144,147 37 included case reports where debridement was necessary60,62,65–67,75,77,78,83,87,91,92,95–97,102,105,108,111,113,117–119,125,127,129,131,132,135,136,148,149,153,154,159,160,162 and 26 studies had case reports that required skin grafts. 60,62,65,67,77,78,83,87,90,92,97,102,105,110,111,117,125,127,131,135,148,153,154,159–161 Only one study reported a skin graft that had not also undergone debridement or a fasciotomy. 110

Outcomes were generally poorly reported and lacking in detail. The majority of studies (n = 90) reported a functional or full recovery for all their participants. 58–67,69–90,92–95,97–110,112,114,116,119–123,125–127,130–132,134,136–147,149–151,153,155–163 However, few of these (n = 25) reported on whether or not adverse outcomes such as scarring occurred. 58,61,65,66,69,71,75,79,81,85,94,97,100,102,105,107,110,114,116,120,130,139,146,150,153 Of these 25 studies, 17 indicated some scarring but how this was reported was inconsistent across studies and was usually vague. 58,61,65,66,69,71,79,85,97,100,102,105,110,130,139,150,153 In addition, the time points at which scars were assessed varied widely across the studies, ranging from within 24 hours to three years.

Summary

Overall, the case reports point to a lack of methodological consistency in the area. Little, if any, information is given about the extent of injury before treatment, and outcomes were measured and reported inconsistently. In a similar vein to the non-comparative studies, inconsistency of treatment variables such as dosage and delay until treatment make any comparisons of the findings of these reports of limited use.

Reviews and guidelines

Reviews

Three reviews, one narrative8 and two systematic,17,164 were identified that synthesised the evidence on treatment for extravasation events and injuries. Clifton-Koeppel8 conducted a broad narrative review of extravasation injuries across a range of patient populations which included a review of initial treatments and subsequent wound care options. The author recommended the use of clinical staging criteria of the severity of wounds to help determine the appropriate treatment. The author also indicated that, although there was agreement that immediate treatment is needed for the best outcomes, there is no consensus regarding which treatments are best. Saline wash-out and hyaluronidase treatments appeared to be frequently studied. The review also reported that reduced wound healing time and scarring can be achieved from the promotion of a moist environment using topical ointments/gels and dressings, while also noting the toxicity problems that may result from using topical treatments in newborns. The local application of heat or cold were not well studied treatments, with no studies found in newborns. Although this review was not systematic (so some relevant studies may have been missed), the author’s conclusions, in which they lament the very limited evidence available and call for further research, nevertheless, seem appropriate.

The second review was a Cochrane systematic review which examined the evidence for a specific type of technique, saline irrigation with or without prior hyaluronidase, on wound care in neonates with extravasation injuries. 17 The authors conducted an extensive search of the literature with clear search criteria to identify randomised controlled trials (RCTs) and quasi-RCTs comparing the intervention with no intervention or normal wound care. Despite the rigorous methodology, the authors found no eligible studies. They repeated the searches without an age restriction but still identified no studies that matched the inclusion criteria. They therefore performed a descriptive review of some case reports, case series and cohort studies. These indicated that several different methods were in current practice for the management of extravasation injuries; therefore, the review authors expressed the opinion of an impression that mild injuries (stages 1 and 2) may heal well under conservative management, whereas more severe injuries (stages 3 and 4) may need more invasive treatment. However, these recommendations are based on a very limited evidence base.

In 2015, Harrold et al. 164 published a systematic review of the management of cytotoxic chemotherapy extravasations. The review focused on strategies aimed at preventing the need for surgical debridement. Six databases were searched and eligibility criteria were specified for including studies in the review. Study quality was evaluated using a levels of evidence approach. The 31 included studies were mostly case series which evaluated dextrazoxane, DMSO, saline wash-out, hyaluronidase or steroids with or without sodium thiosulphate. However, no conclusive evidence was found to favour one strategy over another. The authors noted that, despite this, some ‘expert opinion’ guidelines favour the use of specific antidotes over saline wash-out. The authors also noted that no studies evaluated outcomes relating to patient experience or patient perspective on extravasation management.

Guidelines

The searches identified seven references relating to guidelines on the management of extravasation injuries. 1,2,18,19,165–167 Two of the references165,166 reported on the same set of guidelines but both were available only as conference abstracts, limiting the information that could be extracted from them. Of the remaining five references, one was a general document which included guidelines for all types of extravasation injuries,2 one focused on a paediatric population,19 and the remaining three limited their scope according to the type of fluid extravasated. 1,18,167

Great Ormond Street Hospital published a set of guidelines online, which cover the prevention, recognition and management of extravasation injuries. 2 The guidelines emphasised the need for immediate management of extravasation injuries by immediately stopping the infusion and aspirating the area of the wound, but the device should not be flushed. Plastic surgeons should determine treatment which includes analgesia, as required; elevation of the affected limb; conservative management, which may involve the use of hot or cold compresses, or antidotes; and saline wash-out. Extravasation kits should be available to the plastic surgeon. This guideline made reference to only a few studies that its recommendations were based on. It did not clarify the basis by which studies were selected, and the quality (i.e. strengths/weaknesses) of the studies was not assessed or discussed. The guideline did not state the circumstances where they are best applied and did not report on the potential harms or side effects that may occur from the listed treatments.

Flemmer and Chan19 limited their guidelines to the management of extravasation injuries in paediatric populations. Their article described a hospital treatment protocol developed to identify and treat extravasation injuries. Consistent with other guidelines, they reported on the inconsistency of approaches but discounted the practice of injecting treatments around the infiltrated site, as they argued this made infection and skin breakdown more likely. Rather, they proposed aspirating the wound to remove the extravasated fluid, then infiltrating it with the chosen treatment. They emphasised that appropriate treatment is dependent on the degree of severity of the wound, indicating that a stage 1 or 2 infiltrate can normally be managed conservatively through elevation. They stated that warm or cold packs have not been shown to significantly alter the clinical course. They recommended a more aggressive approach to treating stage 3 and 4 infiltrates, emphasising immediate and intrusive intervention. They recommended hyaluronidase treatment within 2 hours of the injury, together with glyceryl trinitrate (a vasodilator). Phentolamine was considered effective for treating vasoconstrictor extravasations.

Flemmer and Chan’s guideline19 is narrower in scope than Great Ormond Street’s guidelines and is, therefore, somewhat clearer in defining the health question. They stated that they conducted a review of the literature before creating the guideline but it is unclear if the recommendations are made on the basis of the literature search or on the clinical experience of their team. Despite conducting a review, the criteria on which they included studies, the nature of these studies and an assessment of their quality were not reported in the article. Some potential adverse treatment effects were mentioned. The article was published in 1993 and is, therefore, very likely to be out of date.

The guideline published by Bellin et al. 18 was specifically targeted towards contrast medium extravasations. They highlighted infants, young children, unconscious and debilitated patients as being particularly at risk for these types of injuries. Those receiving chemotherapy were also considered at risk because of the fragility of their vein walls. The guidelines stated that there is no consensus regarding treatment but that most extravasations involve small amounts of fluid inducing minimal swelling or redness. However, they emphasised that necrosis and ulceration do occur more commonly with high-volume extravasations than with low-volume extravasations. Despite the acknowledgement of these risk factors, the guidelines argued that it is not possible to predict whether these types of injuries will resolve or worsen at initial examination, but skin blistering, altered tissue perfusion, paraesthesia and persistent pain after 4 hours suggest severe injuries. They suggested that most contrast medium extravasations are not serious and only require conservative management. Silver sulfadiazine ointment was recommended for blistering to prevent secondary infections. Hyaluronidase injections (administered within 1 hour) have been used for large extravasations of contrast medium and chemotherapeutic agents, although conflicting efficacy results have been published. 45–47 DMSO, corticosteroids and vasodilators were mentioned as potential treatments but studies have either failed to demonstrate benefits or treatments have not been tested for extravasations of this type.

Bellin et al. ’s18 guidelines have a clear focus, acknowledge the limitations of the evidence and back up statements by reference to relevant studies. However, similar to the previous guidelines, they do not assess the quality of the studies they base their assertions on nor give the criteria with which they included these studies. This guideline is also somewhat dated, having been published in 2002.

The guideline published by Pérez Fidalgo et al. ,1 which focused primarily on chemotherapy extravasations, emphasised the importance of classifying extravasated fluids by their potential to cause damage (vesicant, irritant and non-vesicant categories were used). The authors noted a number of difficulties in recommending appropriate treatment, including the lack of any RCTs, likely due to ethics complications and potential difficulties in recruiting patients. The authors stated that an extravasation kit containing instructions, materials and medication to handle any incidence should be always available. The guideline covered many treatment options. Hydrocortisone injections have been shown to have some potential in preventing tissue necrosis but intralesion corticoids seem to do more harm than good. Subcutaneous corticoids were, therefore, not recommended. They reported that topical DMSO is an option for treating extravasation of anthracyclines, mitomycin C or platin salts, but the concentration of the drug should be kept low (50%). Dexrazoxane was also recommended for anthracycline extravasations. Hyaluronidase (injected through the existing i.v. line) was recommended to prevent skin necrosis following vinca alkaloid extravasation. Subcutaneous wash-out procedures were also reported to have shown encouraging results. The authors reported that around one-third of cytotoxic extravasations lead to ulceration and, hence, surgical procedures should be limited to those patients where conservative therapy has failed. They recommended surgical debridement of wounds for unresolved necrosis lasting > 10 days, followed by a skin graft where necessary.

These guidelines1 have a precise focus which, although making for a clear definition of the health question, restricts the generalisability to a paediatric population. The authors made no mention of the criteria with which they included the studies on which they based their recommendations. They did, however, provide details of the included studies and made explicit links to the recommendations and the supporting evidence. Levels of evidence gradings were also provided. The guidelines are also relatively current, having been published in 2012.

In 2015, Boulanger et al. 167 published a guideline on the management of antineoplastic agent extravasations to inform clinical practice in Quebec. Studies were identified using a search of PubMed, although few eligibility criteria were stated. Levels of evidence were used to grade recommendations. Separate guidance was made for peripheral line and central line extravasations of specific chemotherapies. Recommendations were similar to those published by Pérez Fidalgo et al. 1 and included dry warm compress, dry cold compress, DMSO, dexrazoxane and hyaluronidase. However, most recommendations were based on studies supported by little or no empirical evidence.

Only abstracts were available for the remaining two guideline articles. 165,166 An algorithm was developed guiding wound care for three potential wound types but little detail was provided. 165

Summary

Of the three reviews identified, none found any substantial comparative studies examining treatment effectiveness. 8,17,164 All reviews agreed that, although immediate treatment is needed for the best outcome, there is no consensus regarding which treatments are the best practice. They all mention saline wash-out with or without hyaluronidase as a frequently studied treatment, but no review could make conclusive statements on its effectiveness compared with other treatments, because of the limited quality of evidence.

Seven published guidelines were discovered which detailed the management of extravasation injuries. 1,2,18,19,165–167 All were limited in their applications to different patient groups and few reported on the potential harms or side effects that may occur from a particular course of treatment. In addition, the criteria on which studies were included and an assessment of the quality of these studies were not reported in any of the published guidelines. Their recommendations were often conflicting on treatments, such as for saline wash-out,1,2 specific antidotes1,19 and conservative management. They did report some similar findings on hyaluronidase as being an effective treatment and on corticosteroids as being an ineffective treatment. They also agreed that treatment should be started as soon as possible after injury.

Overall, the results from the reviews and guidelines that included evidence from studies in adults add little to the evidence seen in the primary studies in babies and children for identifying the most promising treatments for extravasation injuries.

Chapter 3 Survey of NHS practice

The primary aims of the survey were to determine how extravasation injuries in babies and young children are treated across the NHS, and to elicit opinions regarding future research studies.

Results

A total of 63 questionnaires were received from 56 different hospitals. Fifty-five questionnaires (87%) were fully completed and eight (13%) were partially completed. Key summary results relating to each question are presented below. Additional results data for some questions are reported in Appendix 5.

Respondent characteristics

Forty-eight (76%) questionnaires were received from units in England, six (10%) from Scotland, five (8%) from Northern Ireland and two (3%) from Wales. Although the survey was intended to be only of NHS units, the snowballing approach used resulted in two responses from outside the NHS: one from the USA and one from Canada. Given that the responses on these two questionnaires were broadly in line with those from other questionnaires, these data were included in our analyses.

Forty-five (71%) responses were from neonatal units, 13 (21%) were from principal oncology/haematology units and five (8%) were from paediatric intensive care units (PICU). Most responders were either consultant neonatologists (31 responders, 48%), nursing staff (10 responders, 16%) or consultant paediatricians (eight responders, 13%). Details of all responder positions are presented in Table 8.

TABLE 8 - Positions of survey responders

Position	Number (%) of responders
Consultant neonatologist	31 (48)
Nursing staff	10 (16)
Consultant paediatrician	8 (13)
PICU consultant	4 (6)
Consultant paediatric oncologist	2 (3)
Clinical nurse educator	2 (3)
Specialist registrar	2 (3)
Associate specialist	1 (2)
Paediatric registrar	1 (2)
Ward manager	1 (2)
Neonatal midwife	1 (2)

Hospital unit documentation

Does your unit have a written protocol or guideline for treating extravasation injuries?

This answer was analysed at the hospital-unit level (rather than by individual respondents). Overall, of the 57 unit responses to this question, 47 (82%) said they had a written protocol or guideline, nine (18%) said they did not and one (2%) did not know. In neonatal units, 29 (73%) had a written protocol or guideline, 10 (25%) did not and one unit (3%) did not know. All 13 principal oncology/haematology units and all four PICUs had a written protocol or guideline. Units answering ‘yes’ to this question were then asked about the inclusion of an injury severity staging system.

Does the protocol or guideline contain a staging system for grading severity of extravasation injury?

Of the 30 responses from neonatal units, 11 (37%) were ‘yes’, 16 (53%) were ‘no’ and three (10%) were ‘do not know’. Of the 13 principal oncology/haematology unit responses, 5 (38%) were ‘yes’ and 8 (62%) were ‘no’. Of the four PICU responses, one was ‘yes’ and three were ‘no’.

Does your unit have a list which identifies infusates which may cause serious problems when extravasated?

Overall, of the 55 units responding, 39 (71%) did have a list and 16 (29%) did not have a list. For neonatal units, 23 had a list and 16 did not. All 13 principal oncology/haematology unit responses and all three PICU responses were ‘yes’.

Injury parameters

Please select the type of access site most associated with extravasation injuries in your unit’s patients.

Of the 42 responses from individuals in neonatal units, 40 (95%) chose peripheral line and two (5%) chose peripheral central line. Of the 13 principal oncology/haematology unit responses, eight (62%) chose peripheral line, three (23%) indicated that extravasation injuries were too rare to choose an access site option, one (8%) chose central line and one (8%) did not know. All five PICU responses were peripheral line.

Please select the type of infusate which causes the largest proportion of all the extravasation injuries in your unit’s patients.

For this question, more than one answer could be selected if the proportions were equal. For neonatal units, 29 out of the 59 answers (49%) identified parenteral nutrition as the infusate causing the largest proportion of injuries. Other infusates were calcium (nine answers, 15%), blood (8 answers, 14%), do not know (5 answers, 8%), antibiotics (3 answers, 5%), inotropes or pressors (2 answers, 3%), 10% dextrose (2 answers, 3%) and caffeine (1 answer, 2%).

Vesicant chemotherapies caused the largest proportion of injuries in principal oncology/haematology units (9 out of 17 answers, 53%), followed by non-vesicant chemotherapies (three answers, 18%) and blood, saline and sodium bicarbonate (one answer each). One respondent opted for ‘do not know’ and one noted that there were ‘too few incidents to comment’. The seven PICU answers varied, without any infusate dominating; they included parenteral nutrition, calcium, antibiotics, 10% dextrose, ‘sodium benzoate, phenytoin, acyclovir’ and ‘i.v. fluids’.

The following question was asked of those responders selecting parenteral nutrition/calcium/blood or vesicant chemotherapies for the previous question:

What proportion of the extravasation injuries in your unit would you estimate is caused by extravasation of infused parenteral nutrition/calcium/blood/vesicant chemotherapies?

Of the 29 responders from neonatal units who said that parenteral nutrition caused the largest proportion of injuries, most indicated that these injuries constituted a large or very large majority of all the extravasation injuries encountered (Figure 2).

FIGURE 2.

Percentage of neonatal unit extravasation injuries caused by parenteral nutrition in units indicating parenteral nutrition as the main cause of injuries.

For the neonatal unit calcium extravasation responses, 5 out of 9 chose the 75–100% option. For the eight blood extravasation responses, the proportions were more varied (see Appendix 5). Of the principal oncology/haematology unit responses which indicated that vesicant chemotherapies caused the largest proportion of extravasation injuries, 6 out of 9 indicated that the proportions were large (see Appendix 5).

Interventions used to treat extravasation injuries

Please consider the list below of possible treatments for extravasation injuries. How frequently is each of them used in your unit?

The results of neonatal unit responders are reported in Table 9. The most frequently used intervention approaches were elevation of the affected area and administration of analgesics. In most units, warm or cold compresses were rarely or never used. There was notable variation across the responses regarding the use of occlusive dressings, ranging from always being used (8% of responses) to never being used (31% of responses). Variation in the use of saline irrigation, either with or without hyaluronidase, was also evident; these interventions seem to be either usually used or sometimes used in around half of neonatal units, although they are never used in around one-third of units. Results for principal oncology/haematology units (Table 10) and PICUs (Table 11) were broadly similar to the neonatal units results. However, there were some key differences in the principal oncology/haematology unit responses, including a more widespread use of cold and warm compresses and the use of antidotes to specific infusates.

TABLE 9 - Extravasation injury treatments used in neonatal units

Treatment	Number of responses (% of total)					Total number of responders
	Always	Usually	Sometimes	Rarely	Never
Elevation of affected area	12 (29)	12 (29)	13 (31)	4 (10)	1 (2)	42
Warm compress	1(3)	2 (6)	3 (8)	13 (36)	17 (47)	36
Cold compress	1(3)	0	3 (9)	11 (33)	18 (55)	33
Analgesia	9 (21)	19 (45)	10 (24)	4 (10)	0	42
A specific topical cream or ointment	0	3 (8)	7 (19)	6 (17)	20 (56)	36
Occlusive dressing	3 (8)	6 (15)	8 (2)	10 (26)	12 (31)	39
Saline irrigation without hyaluronidase	0	6 (15)	15 (38)	5 (13)	13 (33)	39
Saline irrigation with hyaluronidase	2 (5)	9 (23)	11 (28)	7 (18)	11 (28)	40
Antidotes to specific infusates	0	2 (6)	2 (6)	7 (20)	24 (69)	35

TABLE 10 - Extravasation injury treatments used in principal oncology/haematology units

Treatment	Number of responses (% of total)					Total number of responders
	Always	Usually	Sometimes	Rarely	Never
Elevation of affected area	4 (40)	3 (30)	2 (20)	1 (10)	0	10
Warm compress	2 (22)	1 (11)	5 (56)	0	1 (11)	9
Cold compress	3 (33)	0	5 (56)	0	1 (11)	9
Analgesia	6 (67)	1 (11)	2 (22)	0	0	9
A specific topical cream or ointment	3 (33)	1 (11)	3 (33)	0	2 (22)	9
Occlusive dressing	0	0	3 (38)	1 (13)	4 (50)	8
Saline irrigation without hyaluronidase	1 (11)	0	2 (22)	2 (22)	4 (44)	9
Saline irrigation with hyaluronidase	2 (22)	1 (11)	3 (33)	1 (11)	2 (22)	9
Antidotes to specific infusates	3 (50)	0	1 (17)	0	2 (33)	6

TABLE 11 - Extravasation injury treatments used in PICUs

Treatment	Number of responses (% of total)					Total Number of responders
	Always	Usually	Sometimes	Rarely	Never
Elevation of affected area	4 (80)	1 (20)	0	0	0	5
Warm compress	0	0	0	1 (25)	3 (75)	4
Cold compress	0	0	0	2 (50)	2 (50)	4
Analgesia	3 (60)	1 (20)	1 (20)	0	0	5
A specific topical cream or ointment	1 (25)	0	0	2 (50)	1 (25)	4
Occlusive dressing	0	0	0	2 (40)	3 (60)	5
Saline irrigation without hyaluronidase	1 (20)	0	3 (60)	0	1 (20)	5
Saline irrigation with hyaluronidase	2 (40)	0	2 (40)	1 (20)	0	5
Antidotes to specific infusates	0	0	1 (33)	0	2 (67)	3

Approximately what proportion of extravasations injuries that you have actively treated have resulted in a need for plastic surgery at any stage?

Forty-four of the 59 responders (75%) answered ‘< 5%’. Nine responders (15%) did not know. Four responders answered ‘5–24%’ (three were from neonatal units) and two responders answered ‘> 50%’ (one each from a PICU and a principal oncology/haematology unit).

Litigation

In the last 10 years did any of the extravasation injuries which occurred in your unit result in litigation?

Of the 59 responses to this question, 30 (51%) answered ‘no’, 23 (39%) answered ‘do not know’ and six (10%) answered ‘yes’. The litigation cases related to injuries in three neonatal units, two PICUs and one principal oncology/haematology unit.

For those units which indicated there had been litigation, the following question was asked:

How many litigation cases were there in the last 10 years?

Four units reported one case, one unit did not know the number of cases and one PICU reported six cases.

Research

Regarding a future research study in this area, do you think a randomised trial design can be successfully undertaken to compare different treatments for extravasation injuries in babies and young children?

Of the 57 responses, 37 (65%) thought a future RCT might be viable, 12 (21%) did not think a RCT was viable and eight (14%) did not know. However, the results varied by setting; the proportion answering ‘yes’ to this question was 83% of the 40 neonatal unit responses, 33% of the 12 principal oncology/haematology unit responses (33% also responded ‘no’ and 33% responded ‘do not know’) and 0% of PICUs (of the five responses, three thought ‘no’ and two ‘do not know’).

For those who thought a future RCT was viable, the following question was asked:

Please tell us which treatment(s) you would most like to see studied in a randomised trial.

This was answered using a free text field. Almost all of the 28 responders mentioned one or more treatments: saline irrigation/wash-out, hyaluronidase and conservative management. Few details were given about conservative management approaches, although dressings, analgesia and hydrocolloid were mentioned. Two responders suggested trialling glyceryl trinitrate (GTN): comparing its use with no GTN, or compared with wash-out. The results are best summarised as a word cloud (Figure 3).

FIGURE 3.

Word cloud representing treatment suggestions for a randomised trial.

For those respondents who thought a future RCT was not viable, the following question was asked:

It would be helpful if you could say why a randomised trial design might not be viable. If you have any thoughts on alternative study designs, which you think might be more appropriate, please also state them here.

Of the five responders from neonatal units who did not think a RCT was viable, four provided further details. Two responders referred to there being too many variables, in terms of types of injury and other clinical factors (beyond infusate and volume) which could affect outcomes. One responder noted that, for total parenteral nutrition, the infusates may ‘be very different day by day, or between units’. Issues around timeliness of treatment when using randomisation, low numbers of patients and unwillingness to deviate from current practice were also stated as potential problems.

All the responders from principal oncology/haematology units (n = 4) and PICUs (n = 3) who did not think a RCT was viable provided further details. In principal oncology/haematology units, the rarity of extravasation events was mentioned as a potential problem by two responders. Reluctance to deviate from current practice (‘procedures which are currently working well’) was mentioned by the other two responders; the exception was blood transfusion extravasations where there were no guidelines on appropriate management (mentioned by one responder). In PICUs, the low incidence of injuries was raised as an issue. One responder thought that, although there was no equipoise for a placebo controlled trial, a comparison between two therapeutic options might be viable.

Are you aware of any summary data on the effectiveness or safety of treatments for extravasation injury which we are unlikely to have been identified in our searches of literature databases (e.g. unpublished data)?

None of the 55 responders were aware of any unpublished summary data (46 responded ‘no’ and nine responded ‘do not know’).

Any other comments or suggestions about this study?

Three principal oncology/haematology unit responders mentioned how rare extravasation injuries were, with two stating that they were so rare they struggled to provide answers for some questions (other than ‘do not know’). Three neonatal responders also mentioned the rarity of extravasation events, especially significant injuries (in other words, most of the injuries seen in practice are mild).

One principal oncology/haematology unit responder wanted to stress that their treatment protocol describes very specific management based on the infusate. A responder from a neonatal unit thought that the use of BadgerNet© (Clevermed Ltd, Edinburgh, UK) data would be good in order to study variation in the incidence of extravasation injuries (and the possible reasons for variation).

Chapter 4 Discussion

Chapter 5 Conclusions

Although studies exist that, together, cover a wide range of treatments for extravasation injuries, most studies are small and lack comparator groups. The studies are also very varied in terms of patient, intervention and outcome characteristics. The quality of evidence overall is, therefore, very low. Consequently, there is uncertainty about which treatments are most promising, particularly with respect to treating earlier-stage injuries. Notwithstanding the evidence limitations, the results of studies of flush-out techniques suggest that these treatments may be worthy of further research. This finding was echoed in the NHS survey results, with flush-out techniques, hyaluronidase and conservative management frequently suggested as being the treatments where further study would be most worthwhile.

In planning a future comparative study of extravasation injury treatments, population heterogeneity and low rates and sporadic incidence of injuries are key issues. The most viable population for any randomised trial may, therefore, be preterm neonates receiving i.v. parenteral nutrition at a peripheral site. However, a paucity of standardised relevant outcome measures used in previous studies in neonates is a concern. Outcome measures used in a future study would need to be clinically practicable, yet also demonstrate adequate reliability and validity. Some of the practicalities involved in undertaking a conventional RCT, such as recruiting adequate numbers, avoiding treatment delays and selection bias, could be difficult to overcome. Although a prospective observational database study would maximise the number of patients recruited, and eliminate concerns about treatment delays, its results would inherently be subject to uncertainty because of the likelihood of selection bias. An alternative to a conventional RCT design is the randomised registry trial, which incorporates many of the best aspects of both conventional RCTs and observational database studies. However, a key relevant database – the UK NNRD– does not currently record data on extravasation injuries. Further issues to be considered in any randomised registry trial of neonates include the lack of a protocol or guideline for treating extravasation injuries in 25% of units, and the absence of the use of a staging system for grading injury severity in over half of the units which do have access to a protocol or guideline.

Acknowledgements

We thank both Georgina Mackenzie and Claire Khouja from Centre for Reviews and Dissemination for obtaining papers from The British Library, and Claire Khouja for checking the data extracted for case reports. We thank Nigel Davies from the British Association of Perinatal Medicine for distributing the survey link in an e-mailed newsletter. We thank Alexis Llewellyn and Kristina Dietz from Centre for Reviews and Dissemination for translating papers published in French and German.

References

1. Pérez Fidalgo JA, García Fabregat L, Cervantes A, Margulies A, Vidall C, Roila F. ESMO Guidelines Working Group . Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol 2012;23:vii167-73. https://doi.org/10.1093/annonc/mds294.
2. Extravasation and Infiltration. London: Great Ormond Street Hospital for Children; n.d.
3. Amjad I, Murphy T, Nylander-Housholder L, Ranft A. A new approach to management of intravenous infiltration in pediatric patients: pathophysiology, classification, and treatment. J Infus Nurs 2011;34:242-9. https://doi.org/10.1097/NAN.0b013e31821da1b3.
4. Kostogloudis N, Demiri E, Tsimponis A, Dionyssiou D, Ioannidis S, Chatziioannidis I, et al. Severe extravasation injuries in neonates: a report of 34 cases. Pediatr Dermatol 2015;32:830-5. https://doi.org/10.1111/pde.12664.
5. Wilkins CE, Emmerson AJ. Extravasation injuries on regional neonatal units. Arch Dis Child Fetal Neonatal Ed 2004;89:F274-5. https://doi.org/10.1136/adc.2003.028241.
6. Paquette V, McGloin R, Northway T, Dezorzi P, Singh A, Carr R. Describing Intravenous Extravasation in children (DIVE study). Can J Hosp Pharm 2011;64:340-5. https://doi.org/10.4212/cjhp.v64i5.1069.
7. Hee HI, Lim SL, Tan SS. Infusion technology: a cause for alarm. Paediatr Anaesth 2002;12:780-5. https://doi.org/10.1046/j.1460-9592.2002.00993.x.
8. Clifton-Koeppel R. Wound care after peripheral intravenous extravasation: what is the evidence?. Newborn Infant Nurs Rev 2006;6:202-11. https://doi.org/10.1053/j.nainr.2006.10.001.
9. Thyoka M. Clinical negligence claims in pediatric surgery in England: pattern and trends. Eur J Pediatr Surg 2015;25:66-70. https://doi.org/10.1055/s-0034-1395485.
10. Raine JE, Williams K, Bonser J. An analysis of successful litigation claims in children. Arch Dis Child 2011;96. https://doi.org/10.1136/adc.2011.212563.138.
11. Bhananker SM, Liau DW, Kooner PK, Posner KL, Caplan RA, Domino KB. Liability related to peripheral venous and arterial catheterization: a closed claims analysis. Anesth Analg 2009;109:124-9. https://doi.org/10.1213/ane.0b013e31818f87c8.
12. Roth D. Legally speaking. Pediatric infiltration and extravasation. J Assoc Vasc Access 2006;11. https://doi.org/10.2309/java.11-1-5.
13. Roth D. Extravasation injuries of peripheral veins: a basis for litigation?. J Vasc Access Devices 2003;8:13-9. https://doi.org/10.2309/108300803775307729.
14. Millam DA. Managing complications of i.v. therapy (continuing education credit). Nursing 1988;18:34-43. https://doi.org/10.1097/00152193-198803000-00020.
15. Simona R. A pediatric peripheral intravenous infiltration assessment tool. J Infus Nurs 2012;35:243-8. https://doi.org/10.1097/NAN.0b013e31825af323.
16. Hanrahan K. Hyaluronidase for treatment of intravenous extravasations: implementation of an evidence-based guideline in a pediatric population. J Spec Pediatr Nurs 2013;18:253-62. https://doi.org/10.1111/jspn.12035.
17. Gopalakrishnan PN, Goel N, Banerjee S. Saline irrigation for the management of skin extravasation injury in neonates. Cochrane Database Syst Rev 2012;2. https://doi.org/10.1002/14651858.CD008404.pub2.
18. Bellin MF, Jakobsen JA, Tomassin I, Thomsen HS, Morcos SK, Thomsen HS, et al. Contrast medium extravasation injury: guidelines for prevention and management. Eur Radiol 2002;12:2807-12. https://doi.org/10.1007/s00330-002-1630-9.
19. Flemmer L, Chan JS. A pediatric protocol for management of extravasation injuries. Pediatr Nurs 1993;19:355-8.
20. Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs 2011;27:82-90. https://doi.org/10.1016/j.soncn.2010.11.010.
21. Gault DT. Extravasation injuries. Br J Plast Surg 1993;46:91-6. https://doi.org/10.1016/0007-1226(93)90137-Z.
22. Harrold K, Gould D, Drey N. The efficacy of saline washout technique in the management of exfoliant and vesicant chemotherapy extravasation: a historical case series report. Eur J Cancer Care 2013;22:169-78. https://doi.org/10.1111/ecc.12023.
23. Pare JR, Moore CL. Intravenous infiltration resulting in compartment syndrome: a systematic review [published online ahead of print July 31 2015]. J Patient Saf 2015. https://doi.org/10.1097/PTS.0000000000000233.
24. Beall V, Hall B, Mulholland JT, Gephart SM. Neonatal extravasation: an overview and algorithm for evidence-based treatment. Newborn Infant Nurs Rev 2013;13:189-95. https://doi.org/10.1053/j.nainr.2013.09.001.
25. Pettit J, Hughes K. Neonatal intravenous therapy practices. J Vasc Access Devices 1999;4:7-16. https://doi.org/10.2309/108300899775703689.
26. Restieaux M, Maw A, Broadbent R, Jackson P, Barker D, Wheeler B. Neonatal extravasation injury: prevention and management in Australia and New Zealand – a survey of current practice. BMC Pediatr 2013;13. https://doi.org/10.1186/1471-2431-13-34.
27. Arksey H, O’Malley L. Scoping studies: towards a methodological framework. Int J Soc Res Methodol 2005;8:19-32. https://doi.org/10.1080/1364557032000119616.
28. Levac D, Colquhoun H, O’Brien KK. Scoping studies: advancing the methodology. Implement Sci 2010;5. https://doi.org/10.1186/1748-5908-5-69.
29. Daudt HML, van Mossel C, Scott SJ. Enhancing the scoping study methodology: a large, inter-professional team’s experience with Arksy and O’Malley’s framework. BMC Med Res Methodol 2013;13. https://doi.org/10.1186/1471-2288-13-48.
30. Khalil H, Peters M, Godfrey CM, McInerney P, Soares CB, Parker D. An evidence-based approach to scoping reviews. Worldviews Evid Based Nurs 2016;13:118-23. https://doi.org/10.1111/wvn.12144.
31. Ching DL, Wong KY, Milroy C. Paediatric extravasation injuries: a review of 69 consecutive patients. Int J Surg 2014;12:1036-7. https://doi.org/10.1016/j.ijsu.2014.08.355.
32. Harris PA, Bradley S, Moss AL. Limiting the damage of iatrogenic extravasation injury in neonates. Plast Reconstr Surg 2001;107:893-4. https://doi.org/10.1097/00006534-200103000-00053.
33. Onesti MG, Carella S, Maruccia M, Ciotti M, Scuderi N. The use of hyalomatrix PA in the treatment of extravasation affecting premature neonates. Plast Reconstr Surg 2012;129:219e-221e. https://doi.org/10.1097/PRS.0b013e3182365e16.
34. Nandiolo-Anelone KR, Allah KC, Cissé L, Bankolé SR, Oulaï M, Aké AY. Extravasation injuries in newborns: our experience about 15 cases. Chir Main 2014;33:44-50. https://doi.org/10.1016/j.main.2013.11.007.
35. Mu SC, Lin CH, Sung TC. Calcinosis cutis following extravasation of calcium gluconate in neonates. Acta Paediatr Taiwan 1999;40:34-5.
36. Moon HS, Burm JS, Yang WY, Kang SY. Prognosis of full-thickness skin defects in premature infants. Arch Plast Surg 2012;39:463-8. https://doi.org/10.5999/aps.2012.39.5.463.
37. An B, Ning H. Accidental infusion leakage at subgalea in infants: report of 6 cases. Int J Clin Exp Med 2015;8:11943-6.
38. Wang CL, Cohan RH, Ellis JH, Adusumilli S, Dunnick NR. Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections. Radiology 2007;243:80-7. https://doi.org/10.1148/radiol.2431060554.
39. Sawatzky-Dickson D, Bodnaryk K. Neonatal intravenous extravasation injuries: evaluation of a wound care protocol. Neonatal Netw 2006;25:13-9. https://doi.org/10.1891/0730-0832.25.1.13.
40. Sung KY, Lee SY. Nonoperative management of extravasation injuries associated with neonatal parenteral nutrition using multiple punctures and a hydrocolloid dressing. Wounds 2016;28:145-51.
41. Andrés AM, Burgos L, López Gutiérrez JC, Encinas JL, Díaz M, Rivas S, et al. Treatment protocol for extravasation lesions. Cir Pediatr 2006;19:136-9.
42. Casanova D, Bardot J, Magalon G. Emergency treatment of accidental infusion leakage in the newborn: report of 14 cases. Br J Plast Surg 2001;54:396-9. https://doi.org/10.1054/bjps.2001.3593.
43. Wong KY, Ching D, Milroy C. Paediatric Extravasation Injuries: A Review of 69 Consecutive Patients n.d.
44. Harris PA, Moss AL. Management of extravasation injuries. ANZ J Surg 2002;72. https://doi.org/10.1046/j.1445-2197.2002.02496.x.
45. Cochran ST, Bomyea K, Kahn M. Treatment of iodinated contrast material extravasation with hyaluronidase. Acad Radiol 2002;9:544-6. https://doi.org/10.1016/S1076-6332(03)80288-X.
46. Yan YM, Fan QL, Li AQ, Chen JL, Dong FF, Gong M. Treatment of cutaneous injuries of neonates induced by drug extravasation with hyaluronidase and hirudoid. Iran J Pediatr 2014;24:352-8.
47. Crowther DM, Buck ML, McCarthy MW, Barton VW. Improving pediatric adverse drug event reporting through clinical pharmacy services. J Pediatr Pharmacol Ther 2011;16:285-90. https://doi.org/10.5863/1551-6776-16.4.285.
48. Falcone PA, Barrall DT, Jeyarajah DR, Grossman JA. Nonoperative management of full-thickness intravenous extravasation injuries in premature neonates using enzymatic debridement. Ann Plast Surg 1989;22:146-9. https://doi.org/10.1097/00000637-198902000-00010.
49. Linder RM, Upton J, Osteen R. Management of extensive doxorubicin hydrochloride extravasation injuries. J Hand Surg Am 1983;8:32-8. https://doi.org/10.1016/S0363-5023(83)80048-3.
50. Sivrioğlu N, Irkören S. Versajet hydrosurgery system in the debridement of skin necrosis after Ca gluconate extravasation: report of 9 infantile cases. Acta Orthop Traumatol Turc 2014;48:6-9. https://doi.org/10.3944/AOTT.2014.2941.
51. Upton J, Mulliken JB, Murray JE. Major intravenous extravasation injuries. Am J Surg 1979;137:497-506. https://doi.org/10.1016/0002-9610(79)90121-1.
52. von Heimburg D, Pallua N. Early and late treatment of iatrogenic injection damage. Chirurg 1998;69:1378-82. https://doi.org/10.1007/s001040050588.
53. Weiss Y, Ackerman C, Shmilovitz L. Localized necrosis of scalp in neonates due to calcium gluconate infusions: a cautionary note. Pediatrics 1975;56:1084-6.
54. Linder RM, Upton J. Prevention of extravasation injuries secondary to doxorubicin. Postgrad Med 1985;77:105-9. https://doi.org/10.1080/00325481.1985.11698920.
55. Brown AS, Hoelzer DJ, Piercy SA. Skin necrosis from extravasation of intravenous fluids in children. Plast Reconstr Surg 1979;64:145-50. https://doi.org/10.1097/00006534-197908000-00002.
56. Hanrahan K. Evidence-Based Practice Guideline: Hyaluronidase for Treatment of Intravenous Extravasations. Iowa City, IA: University of Iowa College of Nursing; 2012.
57. Ghanem AM, Mansour A, Exton R, Powell J, Mashhadi S, Bulstrode N, et al. Childhood extravasation injuries: improved outcome following the introduction of hospital-wide guidelines. J Plast Reconstr Aesthet Surg 2015;68:505-18. https://doi.org/10.1016/j.bjps.2014.12.029.
58. Abraham MB, van der Westhuyzen J, Khanna V. Arginine extravasation leading to skin necrosis. J Paediatr Child Health 2012;48:E96-7. https://doi.org/10.1111/j.1440-1754.2011.02074.x.
59. Altan E, Tutar O, Senaran H, Aydın K, Acar MA, Yalçın L. Forearm compartment syndrome of a newborn associated with extravasation of contrast agent. Case Rep Orthop 2013;2013. https://doi.org/10.1155/2013/638159.
60. Altmann S, Damert HG, Schneider W. Clinical manifestation of extravasation caused by infusion and its therapeutic management. Zentralbl Chir 2014;139:83-8. https://doi.org/10.1055/s-0031-1271432.
61. Amano H, Nagai Y, Kowase T, Ishikawa O. Cutaneous necrosis induced by extravasation of arginine monohydrochloride. Acta Derm Venereol 2008;88:310-11. https://doi.org/10.2340/00015555-0420.
62. Amaya R. Use of active Leptospermum honey (ALH) and dehydrated amniotic membrane allograft (DAMA) to manage extravasation wounds in neonates. J Wound Ostomy Continence Nurs 2016;43.
63. Amhaz HH, Buretta K, Jooste EH, Machovec K, Marcus JR, Ames WA. Upper extremity peripheral intravenous line infiltration with concomitant loss of pulses treated with lipoaspiration: a case report. A A Case Rep 2016;7:185-7. https://doi.org/10.1213/XAA.0000000000000381.
64. Aribit F, Laville J, Baron J. Extravasation injuries and subcutaneous aspiration in children. Rev Chir Orthop Reparatrice Appar Mot 2000;86:87-8.
65. Baker GL, Franklin JD. Management of arginine monohydrochloride extravasation in the forearm. South Med J 1991;84:381-4. https://doi.org/10.1097/00007611-199103000-00018.
66. Bassi E, Lonati D, Pandolfi R, Gatti M, Jolliffe VM, Del Forno C. Case of skin necrosis due to arginine monohydrochloride extravasation. J Dermatol 2007;34:198-200. https://doi.org/10.1111/j.1346-8138.2007.00249.x.
67. Bhosale GP, Shah VR. Extravasation injury due to dopamine infusion leading to dermal necrosis and gangrene. J Anaesthesiol Clin Pharmacol 2012;28:534-5. https://doi.org/10.4103/0970-9185.101954.
68. Borman H, Tuncali D, Apak A, Kostakoğlu N. Progressive gangrene of the hand following extravasation of antibiotics associated with hereditary resistance to activated protein C. Ann Plast Surg 1998;41:194-6. https://doi.org/10.1097/00000637-199808000-00014.
69. Boyar V, Handa D, Clemens K, Shimborske D. Clinical experience with Leptospermum honey use for treatment of hard to heal neonatal wounds: case series. J Perinatol 2014;34:161-3. https://doi.org/10.1038/jp.2013.158.
70. Broom A, Schur MD, Arkader A, Flynn J, Gornitzky A, Choi PD. Compartment syndrome in infants and toddlers. J Child Orthop 2016;10:453-60. https://doi.org/10.1007/s11832-016-0766-0.
71. Chait LA, Dinner MI. Ulceration caused by cytotoxic drugs. S Afr Med J 1975;49:1935-6.
72. Chen TK, Yang CY, Chen SJ. Calcinosis cutis complicated by compartment syndrome following extravasation of calcium gluconate in a neonate: a case report. Pediatr Neonatol 2010;51:238-41. https://doi.org/10.1016/S1875-9572(10)60045-9.
73. Chiang MC, Chou YH, Wang CR, Huang CC. Extravasation of calcium gluconate concomitant with osteomyelitis in a neonate. Acta Paediatr Taiwan 2004;45:35-7.
74. Ching DL, Wong KY, Milroy C. Latrogenic calcinosis cutis following a neonatal extravasation injury. Br J Hosp Med 2014;75. https://doi.org/10.12968/hmed.2014.75.5.295.
75. Cho KY, Lee SJ, Burm JS, Park EA. Successful combined treatment with total parenteral nutrition fluid extravasation injuries in preterm infants. J Korean Med Sci 2007;22:588-94. https://doi.org/10.3346/jkms.2007.22.3.588.
76. Cohan RH, Dunnick NR, Leder RA, Baker ME. Extravasation of nonionic radiologic contrast media: efficacy of conservative treatment. Radiology 1990;176:65-7. https://doi.org/10.1148/radiology.176.1.2353113.
77. D’Acunto C, Neri I, Purpura V, Orlandi C, Melandri D. Extravasation injury of balanced electrolyte solution simulates the clinical condition of necrotizing fasciitis: a case report. J Pediatr Surg Case Rep 2015;3:466-8. https://doi.org/10.1016/j.epsc.2015.09.006.
78. Davé AL. Third-degree burn following use of microwave-heated cryogel pack. Clin Pediatr 1993;32:191-2. https://doi.org/10.1177/000992289303200318.
79. Davies J, Gault D, Buchdahl R. Preventing the scars of neonatal intensive care. Arch Dis Child Fetal Neonatal Ed 1994;70:F50-1. https://doi.org/10.1136/fn.70.1.F50.
80. Denkler KA, Cohen BE. Reversal of dopamine extravasation injury with topical nitroglycerin ointment. Plast Reconstr Surg 1989;84:811-13. https://doi.org/10.1097/00006534-198911000-00017.
81. Domizio S, Puglielli C, Barbante E, Sabatino G, Amerio P, Artese O, et al. Calcinosis cutis in a newborn caused by minimal calcium gluconate extravasation. Int J Dermatol 2006;45:1439-40. https://doi.org/10.1111/j.1365-4632.2006.02693.x.
82. Dunn D, Wilensky M. Median and ulnar nerve palsies after infiltration of intravenous fluid. South Med J 1984;77. https://doi.org/10.1097/00007611-198410000-00044.
83. Duray PH, Cuono CB, Madri JA. Demonstration of cutaneous doxorubicin extravasation by rhodamine-filtered fluorescence microscopy. J Surg Oncol 1986;31:21-5. https://doi.org/10.1002/jso.2930310104.
84. Eckersall SJ, Spreadbury PL. Severe forearm oedema after intravenous infusion with a IMED 960 infusion pump. Eur J Anaesthesiol 1996;13:39-41. https://doi.org/10.1097/00003643-199601000-00008.
85. Eroglu A, Uzunlar H. Forearm compartment syndrome after intravenous mannitol extravasation in a carbosulfan poisoning patient. J Toxicol Clin Toxicol 2004;42:649-52. https://doi.org/10.1081/CLT-200026975.
86. Garcia-Alvarez F, Bello ML, Albareda J, Seral F. Neonatal tumoration in the secondary to calcium extravasation. Rev Esp Pediatr 1999;55:279-80.
87. Gibboney W, Lemons JA. Necrotizing fasciitis of the scalp in neonates. Am J Perinatol 1986;3:58-60. https://doi.org/10.1055/s-2007-999829.
88. Govind B, Tete PI, Thomas N. Percutaneous central line extravasation masquerading as an abscess. Indian Pediatr 2014;51:309-10. https://doi.org/10.1007/s13312-014-0384-1.
89. Grabois FS, Voievdca T, Aqcuavita A, Kizlansky V, Saint Genez D, Vidaurreta S. Use of sterile petrolatum for extravasation injury in a premature infant. Arch Argent Pediatr 2008;106:533-5. https://doi.org/10.1590/S0325-00752008000600011.
90. Handler EG. Superficial compartment syndrome of the foot after infiltration of intravenous fluid. Arch Phys Med Rehabil 1990;71:58-9.
91. Hankin FM, Louis DS. Surgical management of doxorubicin (Adriamycin) extravasation. J Pediatr Orthop 1984;4:96-9. https://doi.org/10.1097/01241398-198401000-00018.
92. Harb A, Sawyer A, Pandya A. Erythromycin extravasation mimicking necrotising fasciitis in the infant. Eur J Plast Surg 2010;33:159-61. https://doi.org/10.1007/s00238-010-0401-0.
93. Hasija N, Hazarika AJ, Sokhal N, Kumar S. Tissue necrosis of hand caused by phenytoin extravasation: An unusual occurrence. Saudi J Anaesth 2014;8:309-10. https://doi.org/10.4103/1658-354X.130766.
94. Hey DM, Koontz SE. Azithromycin extravasation in a pediatric patient. J Pharm Technol 2005;21:83-6. https://doi.org/10.1177/875512250502100206.
95. Hironaga M, Fujigaki T, Tanaka S. Cutaneous calcinosis in a neonate following extravasation of calcium gluconate. J Am Acad Dermatol 1982;6:392-5. https://doi.org/10.1016/S0190-9622(82)70035-0.
96. Hirsch SD, Powers JM, Rhodes JL. Neonatal soft tissue reconstruction using a bioengineered skin substitute. J Craniofac Surg 2017;28:489-91. https://doi.org/10.1097/SCS.0000000000003346.
97. Hooke MC. Clinical nurse specialist and evidence-based practice: managing anthracycline extravasation. J Pediatr Oncol Nurs 2005;22:261-4. https://doi.org/10.1177/1043454205279289.
98. Kameo SY, Silva GM, Sawada NO, Hardman GL. Hyaluronidase post extravasation of intravenous vincristine: use in children with cancer. J Nurs UFPE 2015;9:9239-45.
99. Khan I, Rizvi SSA, Malik I, Weinberger B, Puvabanditsin S, Hegyi T. Extravasation of intravenous fluid in a preterm neonate. Consultant 2014;54:188-90.
100. Kishi C, Amano H, Shimizu A, Nagai Y, Ishikawa O. Cutaneous necrosis induced by extravasation of hydroxyzine. Eur J Dermatol 2014;24:131-2. https://doi.org/10.1684/ejd.2013.2251.
101. Kuensting LL. Treatment of intravenous infiltration in a neonate. J Pediatr Health Care 2010;24:184-8. https://doi.org/10.1016/j.pedhc.2010.02.001.
102. Kumar RJ, Pegg SP, Kimble RM. Management of extravasation injuries. ANZ J Surg 2001;71:285-9.
103. Lee HJ, Kwon SH, Choi JW, Park KC, Youn SW, Huh CH, et al. The management of infantile extravasation injury using maternal platelet-rich plasma. Pediatr Dermatol 2013;30:e114-7. https://doi.org/10.1111/j.1525-1470.2012.01815.x.
104. Lehr VT, Lulic-Botica M, Lindblad WJ, Kazzi NJ, Aranda JV. Management of infiltration injury in neonates using duoderm hydroactive gel. Am J Perinatol 2004;21:409-14. https://doi.org/10.1055/s-2004-835309.
105. Leung PC, Cheng CY. Extensive local necrosis following the intravenous use of X-ray contrast medium in the upper extremity. Br J Radiol 1980;53:361-4. https://doi.org/10.1259/0007-1285-53-628-361.
106. Llinares ME, Bermúdez M, Fuster JL, Diaz MS, Gonzalez CM. Toxicity to topical dimethyl sulfoxide in a pediatric patient with anthracycline extravasation. Pediatr Hematol Oncol 2005;22:49-52.
107. Martin PH, Carver N, Petros AJ. Use of liposuction and saline washout for the treatment of extensive subcutaneous extravasation of corrosive drugs. Br J Anaesth 1994;72:702-4.
108. Meszes A, Tálosi G, Máder K, Orvos H, Kemény L, Csoma ZR. Lesions requiring wound management in a central tertiary neonatal intensive care unit. World J Pediatr 2017;13:165-72. https://doi.org/10.1007/s12519-016-0070-6.
109. Mohr LD, Reyna R, Amaya R. Neonatal case studies using active Leptospermum honey. J Wound Ostomy Continence Nurs 2014;41:213-18. https://doi.org/10.1097/WON.0000000000000028.
110. Morrison WA, Hurley JV, Ahmad TS, Webster HR. Scar formation after skin injury to the human foetus in utero or the premature neonate. Br J Plast Surg 1999;52:6-11.
111. Mukherjee GD, Guharay BN. Digital gangrene and skin necrosis following extravasation of infusion fluid. J Indian Med Assoc 1977;68:77-9.
112. Nissim L, Gilbertson-Dahdal D. An unusual complication of an infiltrated intravenous catheter: heterotopic ossification in a newborn. J Radiol Case Rep 2008;2:13-5. https://doi.org/10.3941/jrcr.v2i2.30.
113. Onesti MG, Carella S, Maruccia M, Marchese C, Fino P, Scuderi N. A successful combined treatment with dermal substitutes and products of regenerative medicine in a patient affected by extravasation injury from hypertonic solution. In Vivo 2012;26:139-42.
114. O’Reilly C, McKay FM, Duffty P, Lloyd DJ. Glyceryl trinitrate in skin necrosis caused by extravasation of parenteral nutrition. Lancet 1988;2:565-6.
115. Ozcan A, Baratalı E, Meral O, Ergul AB, Aslaner H, Coskun R, et al. Bullous dermatitis and skin necrosis developing after adrenalin extravasation. Eurasian J Med 2015;47:226-8. https://doi.org/10.5152/eurasianjmed.2015.58.
116. Pantelides NM, Shah AK. Extravasation injury: a simple technique to maintain limb elevation within a Neonatal Intensive Care Unit. J Neonatal Nurs 2013;19:243-5.
117. Park HJ, Kim KH, Lee HJ, Jeong EC, Kim KW, Suh DI. Compartment syndrome due to extravasation of peripheral parenteral nutrition: extravasation injury of parenteral nutrition. Korean J Pediatr 2015;58:454-8. https://doi.org/10.3345/kjp.2015.58.11.454.
118. Phillips RA, Andrades P, Grant JH, Ray PD. Deep dopamine extravasation injury: a case report. J Plast Reconstr Aesthet Surg 2009;62:e222-4. https://doi.org/10.1016/j.bjps.2008.11.064.
119. Raffaella C, Annapaola C, Tullio I, Angelo R, Giuseppe L, Simone C. Successful treatment of severe iatrogenic calcinosis cutis with intravenous sodium thiosulfate in a child affected by T-acute lymphoblastic leukemia. Pediatr Dermatol 2009;26:311-15. https://doi.org/10.1111/j.1525-1470.2008.00776.x.
120. Ravenel SD. Cellulitis from extravasation of calcium gluconate simulating osteomyelitis. Am J Dis Child 1983;137:402-3.
121. Reilly JJ, Neifeld JP, Rosenberg SA. Clinical course and management of accidental adriamycin extravasation. Cancer 1977;40:2053-6.
122. Reynolds BC. Neonatal extravasation injury: case report. Infant 2007;3:230-2.
123. Roberts JR. Cutaneous and subcutaneous complications of calcium infusions. JACEP 1977;6:16-20.
124. Rosales CM, Jackson MA, Zwick D. Malassezia furfur meningitis associated with total parenteral nutrition subdural effusion. Pediatr Dev Pathol 2004;7:86-90. https://doi.org/10.1007/s10024-003-4030-5.
125. Roth W, Eschertzhuber S, Gardetto A, Keller C. Extravasation of propofol is associated with tissue necrosis in small children. Paediatr Anaesth 2006;16:887-9.
126. Rustogi R, Mill J, Fraser JF, Kimble RM. The use of Acticoat in neonatal burns. Burns 2005;31:878-82.
127. Salameh Y, Shoufani A. Full-thickness skin necrosis after arginine extravasation – a case report and review of literature. J Pediatr Surg 2004;39:e9-11.
128. Samiee-Zafarghandy S, van den Anker JN, Ben Fadel N. Topical nitroglycerin in neonates with tissue injury: a case report and review of the literature. Paediatr Child Health 2014;19:9-12.
129. Sanpera I, Fixsen JA, Hill RA. Injuries to the physis by extravasation. A rare cause of growth plate arrest. J Bone Joint Surg Br 1994;76:278-80.
130. Santoshi JA, Pallapati SC, Thomas BP. Hand contracture: an unusual sequel of intravenous fluid extravasation in the neonatal period. J Postgrad Med 2008;54:244-5.
131. Schäfer T, Kukies S, Stokes TH, Levin LS, Donatucci CF, Erdmann D. The prepuce as a donor site for reconstruction of an extravasation injury to the foot in a newborn. Ann Plast Surg 2005;54:664-6.
132. Schie JC, Goodman KL. Treatment of neonatal extravasation injuries using non-contact, low-frequency ultrasound: development of a new treatment protocol. Newborn Infant Nurs Rev 2013;13:42-7.
133. Schumacher HR, Osterman AL, Choi SJ, Weisz PB. Calcinosis at the site of leakage from extravasation of calcium disodium edetate intravenous chelator therapy in a child with lead poisoning. Clin Orthop Relat Res 1987;219:221-5.
134. Sharief N, Goonasekera C. Soft tissue injury associated with intravenous phenytoin in a neonate. Acta Paediatr 1994;83:1218-19.
135. Shenaq SM, Abbase EH, Friedman JD. Soft-tissue reconstruction following extravasation of chemotherapeutic agents. Surg Oncol Clin N Am 1996;5:825-45.
136. Sindal MD, Nakhwa CP. Metastatic Serratia endophthalmitis associated with extravasation injury in a preterm neonate. Oman J Ophthalmol 2015;8:114-16. https://doi.org/10.4103/0974-620X.159261.
137. Siu SLY, Kwong KL, Poon SST, So KT. The use of hyaluronidase for treatment of extravasations in a premature infant. HK J Paediatr 2007;12:130-2.
138. Siwy BK, Sadove AM. Acute management of dopamine infiltration injury with Regitine. Plast Reconstr Surg 1987;80:610-12.
139. Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol 1998;13:246-7. https://doi.org/10.1177/088307389801300512.
140. Sonohata M, Akiyama T, Fujita I, Asami A, Mawatari M, Hotokebuchi T. Neonate with calcinosis cutis following extravasation of calcium gluconate. J Orthop Sci 2008;13:269-72. https://doi.org/10.1007/s00776-007-1217-z.
141. Sonohata M, Asami A, Tsunoda K, Hotokebuchi T. Purple glove syndrome associated with intravenous phenytoin administration in a patient with severe mental and motor retardation. J Orthop Sci 2006;11:409-11. https://doi.org/10.1007/s00776-006-1024-y.
142. Soon SL, Chen S, Warshaw E, Caughman SW. Calcinosis cutis as a complication of parenteral calcium gluconate therapy. J Pediatr 2001;138.
143. Stahl S, Lerner A. Compartment syndrome of the forearm following extravasation of mannitol in an unconscious patient. Acta Neurochir 2000;142:945-6.
144. Spenny ML, Moen KY, Dinulos JG. Acute bullous eruption with compartment syndrome due to intravenous infiltration. Arch Dermatol 2004;140:798-800. https://doi.org/10.1001/archderm.140.7.798.
145. Subedi A, Bhattarai B, Biswas BK, Khatiwada S. Complex Regional Pain Syndrome (CRPS type-1) in an adolescent following extravasation of dextrose containing fluid – an underdiagnosed case. Korean J Pain 2011;24:112-14. https://doi.org/10.3344/kjp.2011.24.2.112.
146. Subhani M, Sridhar S, DeCristofaro JD. Phentolamine use in a neonate for the prevention of dermal necrosis caused by dopamine: a case report. J Perinatol 2001;21:324-6. https://doi.org/10.1038/sj.jp.7200493.
147. Talbot SG, Rogers GF. Pediatric compartment syndrome caused by intravenous infiltration. Ann Plast Surg 2011;67:531-3. https://doi.org/10.1097/SAP.0b013e3182085915.
148. Tilden SJ, Craft JC, Cano R, Daum RS. Cutaneous necrosis associated with intravenous nafcillin therapy. Am J Dis Child 1980;134:1046-8.
149. Tiras U, Erdeve O, Karabulut AA, Dallar Y, Eksioglu HM. Debridement via collagenase application in two neonates. Pediatr Dermatol 2005;22:472-5.
150. Tobin C. Managing an extravasation wound in a premature infant. Wounds UK 2007;3:90-1.
151. Tuncer S, Aydin A, Erer M. Extravasation of calcium solution leading to calcinosis cutis surrounding the dorsal cutaneous branch of the ulnar nerve. J Hand Surg Br 2006;31:288-9. https://doi.org/10.1016/J.JHSB.2005.12.001.
152. Vanwijck R, Lengele B. Liposuction as a help for radiologists. Ann Chir Plast Esthet 1994;39:744-9.
153. von Muhlendahl KE. Complications due to infusions in infants and young children. Lessons from six cases of litigation of the Norddeutsche Schlichtungsstelle fur Arzthaftpflichtfragen. Monatsschr Kinderheilkd 2012;160:988-91.
154. Wada A, Fujii T, Takamura K, Yanagida H, Matsuura A, Katayama A. Physeal arrest of the ankle secondary to extravasation in a neonate and its treatment by the Gruca operation: a modern application of an old technique. J Pediatr Orthop B 2003;12:129-32. https://doi.org/10.1097/01.bpb.0000049576.53117.ae.
155. Wiegand R, Brown J. Hyaluronidase for the management of dextrose extravasation. Am J Emerg Med 2010;28:257.e1-2. https://doi.org/10.1016/j.ajem.2009.06.010.
156. Wolfe MS, North ER. Extravasation of injected calcium solution leading to calcifications in the upper extremity of the neonate. Report of a case. J Bone Joint Surg Am 1983;65:558-9. https://doi.org/10.2106/00004623-198365040-00022.
157. Wong AF, McCulloch LM, Sola A. Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates. J Pediatr 1992;121:980-3. https://doi.org/10.1016/S0022-3476(05)80356-7.
158. Wong KY, Ching D, Milroy C. Iatrogenic Calcinosis Cutis Following a Neonatal Extravasation Injury n.d.
159. Yamamoto Y, Igawa H, Minakawa H, Sugihara T, Yoshida T, Minamimoto T, et al. Reconstruction of iatrogenic dorsal skin defects of hands with reverse forearm flaps. Eur J Plast Surg 1994;17:104-5. https://doi.org/10.1007/BF00176927.
160. Yosowitz P, Ekland DA, Shaw RC, Parsons RW. Peripheral intravenous infiltration necrosis. Ann Surg 1975;182:553-6. https://doi.org/10.1097/00000658-197511000-00003.
161. Zenk KE, Dungy CI, Greene GR. Nafcillin extravasation injury. Use of hyaluronidase as an antidote. Am J Dis Child 1981;135:1113-14. https://doi.org/10.1001/archpedi.1981.02130360021008.
162. Berger PE, Heidelberger KP, Poznanski AK. Extravasation of calcium gluconate as a cause of soft tissue calcification in infancy. Am J Roentgenol Radium Ther Nucl Med 1974;121:109-17. https://doi.org/10.2214/ajr.121.1.109.
163. Beytut D, Ozdamar N, Isler N, Turgut N. Extravasation injury: lokal oxigene therapy application within pediatric intensive care unit. Pediatr Crit Care Med 2014;1:134-5. https://doi.org/10.1097/01.pcc.0000449320.67961.46.
164. Harrold K, Gould D, Drey N. The management of cytotoxic chemotherapy extravasation: a systematic review of the literature to evaluate the evidence underpinning contemporary practice. Eur J Cancer Care 2015;24:771-800. https://doi.org/10.1111/ecc.12363.
165. Phillips A. Peripheral intravenous (PIV) catheter extravasation wound care guidelines. J Pediatr Nurs 2011;26. https://doi.org/10.1016/j.pedn.2011.01.264.
166. Timmons J. Peripheral intravenous catheter extravasation wound care guidelines. J Pediatr Nurs 2011;26. https://doi.org/10.1016/j.pedn.2010.12.033.
167. Boulanger J, Ducharme A, Dufour A, Fortier S, Almanric K. Comité de l’évolution de la pratique des soins pharmaceutiques (CEPSP) . Management of the extravasation of anti-neoplastic agents. Support Care Cancer 2015;23:1459-71. https://doi.org/10.1007/s00520-015-2635-7.
168. Clark L, Fairhurst C, Torgerson DJ. Allocation concealment in randomised controlled trials: are we getting better?. BMJ 2016;355. https://doi.org/10.1136/bmj.i5663.
169. Corbett MS, Moe-Byrne T, Oddie S, McGuire W. Randomization methods in emergency setting trials: a descriptive review. Res Synth Methods 2016;7:46-54. https://doi.org/10.1002/jrsm.1163.
170. Langer SW, Sehested M, Jensen PB. Anthracycline extravasation: a comprehensive review of experimental and clinical treatments. Tumori 2009;95:273-82. https://doi.org/10.1177/030089160909500301.
171. Harwood K, Gonin R. Short term vs long term cooling after doxorubicin (DOX) extravasation: an Eastern Cooperative Oncology Group (ECOG) study. Proceed Am Soc Clin Oncol 1994;13.
172. Kasenda B, von Elm E, You J, Blümle A, Tomonaga Y, Saccilotto R, et al. Prevalence, characteristics, and publication of discontinued randomized trials. JAMA 2014;311:1045-51. https://doi.org/10.1001/jama.2014.1361.
173. Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al. Recruitment to randomised trials: strategies for trial enrollment and participation study. The STEPS study. Health Technol Assess 2007;11. https://doi.org/10.3310/hta11480.
174. Denhoff ER, Milliren CE, de Ferranti SD, Steltz SK, Osganian SK. Factors associated with clinical research recruitment in a pediatric academic medical center – a web-based survey. PLOS ONE 2015;10. https://doi.org/10.1371/journal.pone.0140768.
175. Baiardi P, Giaquinto C, Girotto S, Manfredi C, Ceci A. TEDDY Network of Excellence . Innovative study design for paediatric clinical trials. Eur J Clin Pharmacol 2011;67:109-15. https://doi.org/10.1007/s00228-011-0990-y.
176. van der Lee JH, Wesseling J, Tanck MW, Offringa M. Sequential design with boundaries approach in pediatric intervention research reduces sample size. J Clin Epidemiol 2010;63:19-27. https://doi.org/10.1016/j.jclinepi.2009.07.005.
177. Adaptive Design Clinical Trials for Drugs and Biologics. Draft Guidance. Silver Spring, MD: US Food and Drug Administration; 2010.
178. Brusselaers N, Pirayesh A, Hoeksema H, Verbelen J, Blot S, Monstrey S. Burn scar assessment: a systematic review of different scar scales. J Surg Res 2010;164:e115-23. https://doi.org/10.1016/j.jss.2010.05.056.
179. Nguyen TA, Feldstein SI, Shumaker PR, Krakowski AC. A review of scar assessment scales. Semin Cutan Med Surg 2015;34:28-36. https://doi.org/10.12788/j.sder.2015.0125.
180. Woolacott N, Corbett M, Jones-Diette J, Hodgson R. Methodological challenges for the evaluation of clinical effectiveness in the context of accelerated regulatory approval: an overview. J Clin Epidemiol 2017;90:108-18. https://doi.org/10.1016/j.jclinepi.2017.07.002.
181. Valentine JC, Thompson SG. Issues relating to confounding and meta-analysis when including non-randomized studies in systematic reviews on the effects of interventions. Res Synth Methods 2013;4:26-35. https://doi.org/10.1002/jrsm.1064.
182. Gale C, Modi N. WHEAT trial development group . Neonatal randomised point-of-care trials are feasible and acceptable in the UK: results from two national surveys. Arch Dis Child Fetal Neonatal Ed 2016;101:F86-7. https://doi.org/10.1136/archdischild-2015-308882.
183. van Staa TP, Dyson L, McCann G, Padmanabhan S, Belatri R, Goldacre B, et al. The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials. Health Technol Assess 2014;18. https://doi.org/10.3310/hta18430.
184. Li G, Sajobi TT, Menon BK, Korngut L, Lowerison M, James M, et al. Registry-based randomized controlled trials - what are the advantages, challenges, and areas for future research?. J Clin Epidemiol 2016;80:16-24. https://doi.org/10.1016/j.jclinepi.2016.08.003.
185. Lauer MS, D’Agostino RB. The randomized registry trial – the next disruptive technology in clinical research?. N Engl J Med 2013;369:1579-81. https://doi.org/10.1056/NEJMp1310102.

Appendix 1 Database search strategies

Appendix 2 Studies excluded as being about other extravasations

Seventy studies (63 titles and abstracts and seven full papers) were excluded from the scoping review for being about other types of extravasation. The references of these studies are listed below in alphabetical order.

1.  Adesanya O, Naqvi M. Term neonate with liver laceration, obstructive uropathy, and ascites-secondary to extravasation of total parenteral nutrition: a complication of malpositioned umbilical venous catheter. Glob Pediatr Health 2016;3:2333794X16670494. https://doi.org/10.1177/2333794X16670494

2.  Akar S, Topcuoglu S, Dincer E, Sancak S, Karatekin G, Ovali F. A rare umbilical venous catheter complication miscible with necrotizing enterocolitis: intraperitoneal extravasation of total parenteral nutrition. Guncel Pediatri 2015;13:77–80.

3.  Akkan K, Cindil E, Kilic K, Ilgit E, Onal B, Erbas G. Misplaced central venous catheter in the vertebral artery: endovascular treatment of foreseen hemorrhage during catheter withdrawal. J Vasc Access 2014;15:418–23. https://doi.org/10.5301/jva.5000267

4.  Alia R, Ali H. 2 years follow up of intra-abdominal extravasation of TPN causing liver necrosis in a preterm infant. Arch Dis Child Fetal Neonatal Ed 2014;99(Suppl 1):A65–6.

5.  Altunhan H, Annagur A, Ertugrul S, Yuksekkaya HA, Örs R. Coexistence of congenital chylous ascites and congenital hypothyroidism: case report. Turkiye Klinikleri Journal of Medical Sciences 2012;32:1486–9.

6.  Ancora G, Soffritti S, Faldella G. Diffuse and severe ischemic injury of the extremities: a complication of umbilical vein catheterization. Am J Perinatol 2006;23:341–4. https://doi.org/10.1055/s-2006-946721

7.  Au SH, Sun DC, Lue HC. Cardiac tamponade from percutaneous central venous catheterization: report of one case. Acta Paediatr Taiwan 2003;44:235–7.

8.  Ayalon A, Anner H, Berlatzky Y, Schiller M. A life-threatening complication of the infusion pump. Lancet 1978;1:853–4.

9.  Baker J, Imong S. A rare complication of neonatal central venous access. Arch Dis Child Fetal Neonatal Ed 2002;86:F61–2.

10.  Bala I, Pratap M, Nakra D, Jain K. Retroperitoneal extravasation of i.v. fluid following femoral venepuncture. Paediatr Anaesth 2006;16:803–4.

11.  Been JV, Degraeuwe PL. Pleural effusion due to intra-abdominal extravasation of parenteral nutrition. Pediatr Pulmonol 2008;43:1033–5. https://doi.org/10.1002/ppul.20891

12.  Bergman KA, Doedens R, vd Akker E, Wüst AF. Displacement and extravascular position of a saphenous vein catheter: a serious complication. Eur J Pediatr 1999;158:868–9.

13.  Blackwood BP, Farrow KN, Kim S, Hunter CJ. Peripherally inserted central catheters complicated by vascular erosion in neonates. JPEN J Parenter Enteral Nutr 2016;40:890–5. https://doi.org/10.1177/0148607115574000

14.  Bolton DT. Extravasation associated with a multilumen central catheter. Anaesthesia 1997;52:1119.

15.  Bothur-Nowacka J, Czech-Kowalska J, Gruszfeld D, Nowakowska-Rysz M, Kościesza A, Polnik D, Dobrzańska A. Complications of umbilical vein catherisation. Case Report. Pol J Radiol 2011;76:70–3.

16.  Čače IB, Krajina R, Čače N. Umbilical vein catheterization – when complications occur a case report. Signa Vitae 2014;9:73–5.

17.  Campistol J, Krauel J, Baraibar R. Hydrothorax: a rare complication of parenteral feeding in a new born. Z Kinderchir 1980;29:251–3.

18.  Coley BD, Seguin J, Cordero L, Hogan MJ, Rosenberg E, Reber K. Neonatal total parenteral nutrition ascites from liver erosion by umbilical vein catheters. Pediatr Radiol 1998;28:923–7. https://doi.org/10.1007/s002470050500

19.  Currarino G. Migration of jugular or subclavian venous catheters into inferior tributaries of the brachiocephalic veins or into the azygos vein, with possible complications. Pediatr Radiol 1996;26:439–49.

20.  Das D, Datta M, Dey S, Parida J, Kumar R, Pande A. An unusual cause of cardiac tamponade during cardiac catheterization study. Case Rep Cardiol 2014;2014:652592. https://doi.org/10.1155/2014/652592

21.  D’Elia C, Correia MS, de Oliveira SD, Barbosa NM. Bronchovascular fistula – complication of percutaneous central venous catheter in a neonate. J Pediatr 2002;78:347–50.

22.  Department of Health and Social Care. Review of Four Neonatal Deaths due to Cardiac Tamponade Associated with the Presence of a Central Venous Catheter: Recommendations and Department of Health and Social Care Response. London: Department of Health and Social Care; 2001.

23.  Edmonds LK, Craw S. Extravasation & UVC’s: a cautionary case series. J Paediatr Child Health 2015;51(Suppl 1):92.

24.  Gomes ACR, da Silva CAG, Gamarra CJ, Faria JCdO, Avelar AFM, Rodrigues EdC. Assessment of phlebitis, infiltration and extravasation events in neonates submitted to intravenous therapy. Anna Nery School Journal of Nursing 2011;15:472–9.

25.  Gonzalez-Tarancon R, Lasierra Monclus AB, Murillo Peruga O, Garcia-Rodriguez B, Puzo Foncillas J. Hydrothorax in an infant induced by central venous catheter malposition after cardiac surgery. A case report. Revista del Laboratorio Clinico 2015;8:127–30.

26.  Grizelj R, Vukovic J, Bojanic K, Loncarevic D, Stern-Padovan R, Filipovic-Grcic B, et al. Severe liver injury while using umbilical venous catheter: case series and literature review. Am J Perinatol 2014;31:965–74. https://doi.org/10.1055/s-0034-1370346

27.  Guzoglu N, Erdeve O, Yilmaz Y, Dilmen U. Intraperitoneal extravasation from umbilical venous catheter in differential diagnosis of neonatal chylous ascites. Acta Paediatr 2010;99:1284. https://doi.org/10.1111/j.1651-2227.2010.01893.x

28.  Haass C, Sorrentino E, Tempera A, Consigli C, De Paola D, Calcagni G, et al. Cardiac tamponade and bilateral pleural effusion in a very low birth weight infant. J Matern Fetal Neonatal Med 2009;22:137–9. https://doi.org/10.1080/14767050802509561

29.  Hager J, Menardi G. Retroperitoneal extravasation – rare complication with parenteral nutrition (author’s transl). Padiatr Padol 1981;16:227–31.

30.  Hagerott HE, Kulkarni S, Restrepo R, Reeves-Garcia J. Clinical-radiologic features and treatment of hepatic lesions caused by inadvertent infusion of parenteral nutrition in liver parenchyma due to malposition of umbilical vein catheters. Pediatr Radiol 2014;44:810–15. https://doi.org/10.1007/s00247-014-2895-2

31.  Hanta D, Gulcan H, Torer B, Ozdemir Z, Temiz A. Neonatal total parenteral nutrition ascites following umbilical venous catheterization in a preterm newborn. Early Hum Dev 2010;86:S82–3.

32.  Jardine LA, Inglis GD, Davies MW. Aspiration of parenteral nutrition – a previously unreported complication of central venous access in an infant: a case report. J Med Case Rep 2008;2:63. https://doi.org/10.1186/1752-1947-2-63

33.  Keeney SE, Richardson CJ. Extravascular extravasation of fluid as a complication of central venous lines in the neonate. J Perinatol 1995;15:284–8.

34.  Kingsley DP, Kendall BE, Greitz T, Hoare RD. Extravasation of contrast-enhanced blood into the subarachnoid space during computed tomography. Neuroradiology 1979;18:259–62.

35.  Knobel RB, Meetze W, Cummings J. Case report: total parenteral nutrition extravasation associated with spinal cord compression and necrosis. J Perinatol 2001;21:68–71.

36.  Korver AM, Walther FJ, van der Molen AJ, de Beaufort AJ. [Serious complications of umbilical venous catheterisation.] Ned Tijdschr Geneeskd 2007;151:2219–23.

37.  Krasna IH, Krause T. Life-threatening fluid extravasation of central venous catheters. J Pediatr Surg 1991;26:1346–8.

38.  Kreusser KL, Volpe JJ. Peroneal palsy produced by intravenous fluid infiltration in a newborn. Dev Med Child Neurol 1984;26:522–4.

39.  Krüse-Ruijter MF, Robben SG, Degraeuwe PL. Hydrocoele and periorchitis after extravasation of parenteral nutrition solution. Arch Dis Child Fetal Neonatal Ed 2011;96:F359. https://doi.org/10.1136/adc.2011.210914

40.  Kundra P, Chandran BV, Subbarao KS. Unanticipated complication of a malpositioned central venous catheter. J Anesth 2009;23:275–7. https://doi.org/10.1007/s00540-008-0724-1

41.  Kurepa D, Sankararaman S, Patra K, Kakkilaya V, Thomas G. Pleural effusion caused by ‘correctly’ placed umbilical venous catheter. J Investig Med 2011;59:454.

42.  Lee SD, Kao TH, Cheng WY, Wang YC. Malposition of central venous catheter eliciting fluid leakage in the lumbar wound: a case report. Formosan J Surg 2001;34:153–7.

43.  Lin C, Elsey N, Corridore M, Grischkan J, Shiels WE, Tobias JD. Dye extravasation during radiography for branchial cleft sinus compromising airway in an infant. Anaesth Pain Intensive Care 2015;19:192–5.

44.  Mahajan V, Rahman A, Tarawneh A, Sant’anna GM. Liver fluid collection in neonates and its association with the use of a specific umbilical vein catheter: report of five cases. Paediatr Child Health 2011;16:13–15.

45.  Meeks SL, Ciambotti JM, Rodgers BM, Gordon PV. Extravasation of hyperalimentation into the liver parenchyma from a peripherally inserted central catheter. J Pediatr Surg 2003;38:E8. https://doi.org/10.1053/jpsu.2003.50146

46.  Nadroo AM, al-Sowailem AM. Extravasation of parenteral alimentation fluid into the renal pelvis – a complication of central venous catheter in a neonate. J Perinatol 2001;21:465–6.

47.  Namachivayam P, Tibballs J. Methylene blue for diagnosis of displaced atrial lines. Anaesth Intensive Care 2006;34:280–1.

48.  Nath MP, Gupta S, Chakrabarty A. Extravasation of catheter tip following central venous catheterisation: a near fatal complication. Indian J Anaesth 2010;54:572–3. https://doi.org/10.4103/0019-5049.72651

49.  Nour S, Puntis JW, Stringer MD. Intra-abdominal extravasation complicating parenteral nutrition in infants. Arch Dis Child Fetal Neonatal Ed 1995;72:F207–8.

50.  Onal EE, Saygili A, Koc E, Turkyilmaz C, Okumus N, Atalay Y. Cardiac tamponade in a newborn because of umbilical venous catheterization: is correct position safe? Paediatr Anaesth 2004;14:953–6.

51.  Ozdemir R, Oğuz S, Uras N, Erdeve O, Yilmaz Y, Ulu H, Dilmen U. Phrenic nerve injury due to thoracentesis for TPN effusion in a preterm newborn: consecutive two unusual complications. Tuberk Toraks 2011;59:384–7.

52.  Oztan MO, Ilhan O, Abay E, Koyluoglu G. An umbilical venous catheter complication presented as acute abdomen: case report. Arch Argent Pediatr 2016;114:e429. https://doi.org/10.5546/aap.2016.eng.e429

53.  Perry MS, Billars L. Extravasation of hyperalimentation into the spinal epidural space from a central venous line. Neurology 2006;67:715.

54.  Pignotti MS, Messeri A, Donzelli G. Thoracentesis in pericardial and pleural effusion caused by central venous catheterization: a less invasive neonatal approach. Paediatr Anaesth 2004;14:349–51. https://doi.org/10.1046/j.1460-9592.2003.01225.x

55.  Rizzo AJ, Haller JO, Mulvihill DM, Cohen HL, Da Silva MG. Calcification of the ductus venosus: a cause of right upper quadrant calcification in the newborn. Radiology 1989;173:89–90. https://doi.org/10.1148/radiology.173.1.2675191

56.  Sankararaman S, Kurepa D, Kakkilaya V, Patra K, Gates T. Pleural effusion: an extremely uncommon complication of correctly placed umbilical venous catheter. J Neonatal Perinatal Med 2012;5:269–73.

57.  Schiavetti A, Ventriglia F. Contrast echocardiography test for intrapleural extravasation by central venous catheter. Imaging Med 2014;6:21–4.

58.  Scott JJ, Ireland S, Kandasamy Y. Conservative management of TPN extravasation into the liver from UVC: a case series. J Paediatr Child Health 2015;51(Suppl 1):92.

59.  Servetar EM. A case report of Twiddler’s syndrome in a pediatric patient. J Pediatr Oncol Nurs 1992;9:25–8. https://doi.org/10.1177/104345429200900105

60.  Shareena I, Khu YS, Cheah FC. Intraperitoneal extravasation of total parental nutrition infusate from an umbilical venous catheter. Singapore Med J 2008;49:e35–6.

61.  Spicer KM, Gordon L. Extravasation from venous catheter: a serious complication potentially missed by lung imaging. J Nucl Med 1983;24:1023–6.

62.  Spriggs DW, Brantley RE. Thoracic and abdominal extravasation: a complication of hyperalimentation in infants. AJR Am J Roentgenol 1977;128:419–22. https://doi.org/10.2214/ajr.128.3.419

63.  Sztajnbok J, Troster EJ. Acute abdomen due to late retroperitoneal extravasation from a femoral venous catheter in a newborn. São Paulo Med J 2002;120:59–61.

64.  Tosello B, Michel F, Merrot T, Chaumoître K, Hassid S, Lagier P, Martin C. Hemidiaphragmatic paralysis in preterm neonates: a rare complication of peripherally inserted central catheter extravasation. J Pediatr Surg 2011;46:E17–21. https://doi.org/10.1016/j.jpedsurg.2011.03.065

65.  van der Putten ME, Been JV, Robben SGF, Zimmermann LJI. An unusual cause of hydronephrosis in a preterm infant. Neth J Crit Care 2011;15:149–51.

66.  Vidwans A, Neumann DP, Hussain N, Rosenkrantz T, Sanders MR. Diagnosis and management of spinal epidural space extravasation complicating percutaneous central venous line placement in a premature infant: case report and review of literature. Conn Med 2000;64:79–82.

67.  Watterson J, Heisel M, Cich JA, Priest JR. Intrathoracic extravasation of sclerosing agents associated with central venous catheters. Am J Pediatr Hematol Oncol 1988;10:249–51.

68.  Williams JH, Hunter JE, Kanto WP, Bhatia J. Hemidiaphragmatic paralysis as a complication of central venous catheterization in a neonate. J Perinatol 1995;15:386–8.

69.  Yeh J, Vargas JH, Wozniak LJ, Smith JB, Ines Boechat M, Touma M. Massive liver mass and parenteral nutrition extravasation secondary to umbilical venous catheter complications. J Clin Neonatol 2014;3:158–60.

70.  Yeoh HA, Chou YH, Wong HF. Migration of a central venous catheter into pulmonary vein complicated with lung edema in a premature infant. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1997;38:303–5.

Appendix 3 Case report study details

Further details of the included case reports are presented in Table 12.

Appendix 4 Survey questionnaire content

The full questionnaire is detailed in Table 13.

Appendix 5 Further questionnaire results

Graphs summarising responses to the question ‘What proportion of the extravasation injuries in your unit would you estimate is caused by extravasation of infused calcium/blood/vesicant chemotherapies?’ (asked of those responders selecting calcium/blood or vesicant chemotherapies for the previous question) are summarised in Figures 4–6.

FIGURE 4.

Percentage of neonatal unit extravasation injuries caused by calcium in units, indicating calcium as the main cause of injuries.

FIGURE 5.

Percentage of neonatal unit extravasation injuries caused by blood in units, indicating blood as the main cause of injuries.

FIGURE 6.

Percentage of principal oncology/haematology unit extravasation injuries caused by vesicant chemotherapies in units, indicating vesicant chemotherapies as the main cause of injuries.

List of abbreviations

AHRQ

Agency for Healthcare Research and Quality

BAPM

British Association of Perinatal Medicine

BNI

British Nursing Index

CCLG

Children’s Cancer and Leukaemia Group

CDSR

Cochrane Database of Systematic Reviews

CENTRAL

Cochrane Central Register of Controlled Trials

CINAHL Plus

Cumulative Index to Nursing and Allied Health Literature

DARE

Database of Abstracts of Reviews of Effects

DMSO

dimethyl sulfoxide

EMBASE

Excerpta Medica dataBASE

GTN

glyceryl trinitrate

HTA

Health Technology Assessment

i.v.

intravenous

MeSH

medical subject heading

NICE

National Institute for Health and Care Excellence

NICU

neonate intensive care unit

NNRD

National Neonatal Research Database

PICU

paediatric intensive care unit

RCT

randomised controlled trial

VSS

Vancouver Scar Scale

WHO

World Health Organization