Keywords
platelet-rich plasma - burns - skin transplantation
Burn injuries are painful and could lead to morbidity through complications such as
pain, infection, dyspigmentation, scarring, psychological conditions, and others.[1] Activated autologous platelet-rich plasma (aaPRP) is an interesting alternative
to tackle these problems associated with burn injuries. aaPRP contains abundant growth
factors, which are able to compensate for the depleted growth factors in wounds and
provide an ideal microenvironment for wound repair.[2] We present seven cases of mid-dermal and full-thickness burns that were treated
with intralesional and intravenous (IV) aaPRP to demonstrate its therapeutic effects
through wound re-epithelialization, anti-inflammation, and pain relief.
Case
This study reports a case series of seven patients with varying degrees of burns.
The aaPRP was prepared with a method that our group developed. Exactly 24 mL of blood
was distributed into eight tubes containing sodium citrate and centrifuged at 1,000 rpm
for 10 minutes. The plasma portion was drawn and recentrifuged at 3,000 rpm for 10 minutes.
The platelet-poor portion was then discarded, leaving a concentrate of 2.5 mL in each
tube (with ∼8.85 times more platelets than whole blood). Precisely 0.15 mL of calcium
activator (H-Remedy, HayandraLab, Indonesia) was added to each tube to activate the
PRP, and the subsequent clots were removed. Finally, 10 mL of normal saline was added
into each tube, and photoactivation (AdiLight-1, AdiStem Ltd., Hong Kong) was performed
afterward. This processing method rendered the aaPRP devoid of leukocytes and platelets,
and it was also suitable for subsequent IV administration.
For subcutaneous (SC) administration, we injected multiple doses of 0.1 mL of aaPRP.
The injections were performed at the edge of the wound, with each injection 1 to 2 cm
apart from the other. We also injected 0.1 mL of aaPRP at the center of the wound
with a similar technique. The remaining aaPRP was then suspended in 100 mL of saline
and delivered intravenously. In patients with a large wound area, the same dose of
SC aaPRP was administered, but the distance between each injection was adjusted.
Case 1
A 43-year-old man presented with bilateral deep-dermal and full-thickness burns on
his legs (18% of the total body surface area [TBSA]). Surgical debridement was performed
5 days after the flame burn injury. aaPRP therapy was then given via SC injection
and IV infusion. The wound was dressed with paraffin gauze and dry gauze. The second
dose of aaPRP was given on the 14th day postinjury. On the 18th day, the patient was
discharged, and 100% epithelization was seen on the 23rd day ([Fig. 1]).
Fig. 1 Bilateral deep-dermal and full-thickness burns on the legs. (A,B) Initial presentation with (B) subsequent photograph after debridement and activated autologous platelet-rich plasma
(aaPRP) therapy. (C) A photograph after the second dose of aaPRP on the 14th day. (D) A photograph showing full re-epithelialization of both legs on the 23rd day.
Case 2
A 28-year-old man presented with deep-dermal burns on both forearms and hands (8%
of the TBSA) due to flame. The wound was debrided on the third day postinjury and
aaPRP was administered locally by SC injection and systemically by IV infusion. The
second aaPRP dose was given on the ninth day postinjury. On the 21st day, the patient
was discharged, and complete wound epithelialization was seen on the 26th day ([Fig. 2]).
Fig. 2 Bilateral deep-dermal burns on the forearms and hands. The (A) right and (B) left posterior side along with the (C) right and (D) left anterior side of the forearm and hands after treatment on the third day. Full
re-epithelialization on the (E) posterior and (F) anterior side of both forearm and hands on the 26th day postinjury.
Case 3
A 38-year-old woman presented 2 days after experiencing deep-dermal and full-thickness
burn on the lateral side of her left superior and inferior extremities. The burn comprised
13% of the patient's TBSA. On the fourth day postinjury, debridement was performed,
followed by SC and IV aaPRP administration. A second dose was given on the 15th day
postinjury. At 6 weeks postinjury, 100% epithelialization was observed. Long-term
follow-up revealed a hypertrophic scar over the knee and elbow joint ([Fig. 3]). The hypertrophic scar was subsequently treated with corticosteroid injection.
Fig. 3 Deep-dermal and full-thickness burns on the left extremities. Initial presentation
at 2 days after injury of the (A) left inferior and (D) superior extremities. A photograph of the patient's (B) left inferior and (E) superior extremities after treatment on the fourth day. Subsequent follow-up of
the (C) left inferior and (F) superior extremities at 9 months postinjury showing hypertrophic scarring.
Case 4
A 42-year-old woman with a 3% TBSA mid-dermal burn presented 10 days after a flame
injury to her left ventral arm and forearm along with signs of local infection (erythema,
tenderness around the wound, and edema). The patient experienced severe pain (numerical
rating scale [NRS] 6) that discouraged her from extending her arm. On the same day,
the wound was debrided and was treated with SC and IV aaPRP. On the 13th day postinjury,
the patient reported relief from pain, and full epithelialization of the wound was
observed ([Fig. 4]). Mobility also returned, as the patient's arm could be extended comfortably.
Fig. 4 Mid-dermal burn on the left arm and forearm. (A) Initial presentation with signs of local infection. (B) Return of mobility and complete epithelialization at 13 days postinjury.
Case 5
A 25-year-old woman experienced a 1% TBSA superficial-dermal burn on the dorsal aspect
of the right hand. She was admitted to our clinic 7 days after a scalding injury and
treated with SC and IV aaPRP. The patient's hand mobility was limited due to severe
pain (NRS 7) and inflammation. On the 10th day postinjury, no edema or inflammation
was present on her hand. Hand mobility was regained as the patient was not in pain
(NRS 0). Furthermore, 100% epithelialization of the affected area was observed ([Fig. 5]).
Fig. 5 Superficial-dermal burn of the dorsal right hand. (A) Anteroposterior and (B) oblique views of the hand at initial presentation. (C) Anteroposterior and (D) oblique views of the hand just 3 days after activated autologous platelet-rich plasma
therapy.
Case 6
A 24-year-old man suffered an extensive deep-dermal and full-thickness burn injury
14 hours before presentation on both of his legs and the back of his left forearm
and hand, comprising 44% of the TBSA. Surgical debridement was performed on the 1st
day postinjury, administration of SC and IV aaPRP on the 1st and 14th days, escharotomy
on the 6th and 16th days, and nonsurgical debridement on the 10th, 23rd, and 26th
days postinjury. The patient was discharged on the same day as the last procedure
with a 99% epithelialization rate ([Fig. 6]).
Fig. 6 Deep-dermal and full-thickness burns on the extremities. Initial presentation of
a burn injury on the (A) left forearm and (C) both legs. Photograph presenting the condition of the (B) left forearm and (D) both legs 9 days after the second activated autologous platelet-rich plasma dose
at 23 days postinjury.
Case 7
A 24-year-old man presented with deep-dermal and full-thickness burns inflicted 6 hours
prior to hospitalization. The burns, which comprised 35% of the TBSA, were present
on his bilateral anterior thighs, anterior left forearm, anterior right forearm, and
posterior right forearm. Surgical debridement was performed upon hospitalization,
escharotomy on the 3rd and 5th days postinjury, nonsurgical debridement on the 8th
and 11th days, and aaPRP on the 2nd and 16th days. Additionally, a microbiology culture
was also performed on the 15th day with samples taken from the patient showing infection
by multidrug-resistant Staphylococcus. The patient was discharged on the 24th day with 100% epithelialization rate ([Fig. 7]).
Fig. 7 Deep-dermal and full-thickness burns on the extremities. Initial presentation of
a burn injury on the (A) anterior side of both thighs, (C) the anterior side of the left forearm, and (D) the anterior and (E) posterior side of the right forearm. Photographs of the anterior side of (B) both thighs and the (F) anterior side and (G) posterior side of both forearms at 5 days after discharge.
Informed consent was obtained from all the patients to include them in this case series
and to publish their clinical photographs. No skin grafting procedures were done in
any cases. Patients with deep-dermal and full-thickness burns were treated with aaPRP
without skin grafting due to informed refusal. IV analgesics were given during hospitalization,
whereas oral analgesics were given in the outpatient setting. Oral cephalosporin was
given to patients if there were signs of infection. The last two cases required more
intense antibiotic use to curb the infection. Patient 6 received ceftriaxone, ampicillin,
and sulbactam, whereas patient 7 received ceftriaxone, ampicillin, sulbactam, vancomycin,
and meropenem.
Discussion
Wound healing, pain, infection, and scarring remain as challenges in the management
of burn injuries.[1] aaPRP is processed autologous plasma that is enriched in platelets. It contains
growth factors and is frequently employed to accelerate wound healing, including burn
wounds.[3] Among the numerous growth factors present in aaPRP are platelet-derived growth factor,
vascular endothelial growth factor, and epidermal growth factor.[3] aaPRP also exerts anti-inflammatory effects through the presence of cytokines, such
as interleukin receptor antagonist and broad antibacterial effects through proteins
such as connective tissue–activating peptide-III.[4]
[5] It has been used in several clinical studies involving soft and hard tissue injuries,
as well as burn wounds.[2]
[6]
[7]
Wound closure is an important factor in burn injuries. Early wound closure reduces
the risk of infection, fluid loss, mortality, and hypertrophic scarring.[8] Our previous study in Sprague-Dawley rats with burn injuries showed that intradermal
injection of PRP promoted tissue regeneration, although its performance was still
inferior in comparison to a PRP–stromal vascular fraction combination.[7] A porcine full-thickness wound model showed that the intrinsic contents of PRP promote
extracellular matrix formation and organization, angiogenesis, and re-epithelialization.[9] In cases 1, 2, 4, 5, and 7, intralesional and IV aaPRP therapy resulted in complete
wound epithelialization before the fourth week.
Burn injuries cause pain by damaging peripheral sensory neurons and inducing inflammation
by proinflammatory mediators.[10] As we described earlier, aaPRP administration attenuated pain due to burn injuries.
This amelioration in pain could be attributed to the anti-inflammatory properties
of aaPRP. Beyond its applications for nociceptive burn pain due to inflammation, Huang
et al[11] also demonstrated that PRP may be beneficial for burn-induced neuropathic pain,
which develops in 6% of patients with burn injuries over 5 years.[12]
Infection is the second most common cause of mortality in burn injuries. The rise
of multidrug organisms necessitates innovations in increasing the effectiveness of
current antimicrobials to improve burn injury morbidity and mortality rates.[1] Infection by S. hominis, which occurred in patient 7, accounts for around 50% of Gram-positive bacterial
infections in Indonesian burn patients.[13] The microbe responsible for infection was found to be resistant to all but one of
the tested drugs (co-trimoxazole). In vitro and in vivo studies have previously confirmed
the antibacterial properties of aaPRP. Although its exact mechanism has yet to be
fully elucidated, aaPRP has the potential to be used as an adjunct to antibiotics
for treatment of infections in burn injuries.[5]
In our patients, we did not perform split-thickness skin grafting (STSG). Usually,
when burns are categorized as deep-dermal and full-thickness burns, skin grafting
is done with prior debridement.[1] Pigmentation mismatch is a common complication with skin grafts, especially in STSG.
In addition, grafting has risks such as donor and transplant site morbidity (scar,
discoloration, hair loss at the donor site, and hair growth at the recipient area).[1]
[14] It is important to note that the application of STSG is restricted in patients with
severe burn injuries that comprise more than 50% of the TBSA as donor skin is very
limited in such cases.[1] In our series, aaPRP treatment promoted wound healing and reduced inflammation.
This opens the possibility for aaPRP to serve as an alternative to skin grafting in
deep burns where such a procedure is not an option, and it is also potentially beneficial
in superficial burns.
When there is an insufficiency of donor skin, meshing is frequently done. Although
meshing has several advantages such as covering a larger area for a smaller area of
harvested skin, allowing fluid drainage, and increasing the edges for re-epithelialization,
it has certain disadvantages. Meshing affects the original graft quality and can result
in severe scarring. Furthermore, grafts that are subjected to meshing heal by secondary
intention, which may result in contracture. Moreover, meshing is also aesthetically
unfavorable as the recipient area heals with a checkered appearance.[1]
[14] Based on our clinical experience, improving the mottled appearance of skin grafts
is rather challenging in comparison to hypertrophic scar revision.
Although neither skin grafting nor meshing was not done in this case series, the utilization
of PRP as a supplementary treatment to improve skin grafting outcomes is well documented.[15] In the cases where epithelialization by aaPRP administration was predicted to be
insufficient within 14 days, we opine that STSG should be considered. The rationale
behind the utilization of aaPRP is to minimize the skin area in need of grafting,
which in turn avoids the meshing or stamping of skin grafts and its aforementioned
drawbacks. Thus, a complementary synergism—which could be taken advantage of—exists
between aaPRP and STSG in the management of burn injuries.
Hypertrophic scars are the most common type of scar following burns. These scars pose
a rehabilitative challenge and delay patients' reintegration into society, ultimately
decreasing their quality of life.[1] Previous studies employing PRP for scar management showed promising results.[16] In vitro, aaPRP lessens hypertrophic scar formation by downregulation of connective
tissue growth factor through activation of the transforming growth factor-β1 signaling
negative feedback mechanism.[17] Furthermore, a prolonged state of acute inflammation and delayed healing have been
shown to induce pathological scarring or bacterial infection. Equine model research
showed that wounds treated with PRP did not exhibit prolonged inflammation.[18]
[19] This anti-inflammatory effect also counters systemic inflammation, which hinders
the wound healing process through slower re-epithelialization and commonly occurs
in severe burn patients.[20]
In our series, we could not evaluate the scar outcomes because we did not perform
long-term follow-up, except for patient 3, who developed hypertrophic scars at 9 months
postinjury. A plausible explanation is that the location of the burn (which was at
a major and highly-mobile joint) caused a slower healing process, hence contributing
to scar formation. However, as previously stated, hypertrophic scars are more manageable
than meshed or stamped skin. Furthermore, as skin grafting was not done, none of our
patients experienced any donor scar morbidity.
Treatment with aaPRP ameliorates burn injury outcomes through various means, improving
overall patient quality of life. It is also a safe procedure that has the potential
to be an alternative treatment in the cases where skin grafting cannot be done or
as an adjunct when skin grafting is performed. Since this series is preliminary in
nature, the optimal aaPRP dosing has yet to be determined. However, in the previous
section, we have shared the empirical optimal dosing and frequency.
Although the results with our patients are encouraging, the limitations of this study
are clear. The lack of long-term outcome data made long-term evaluations of the wounds
impossible. In addition, as no recommendation currently exists, there was no standardization
of aaPRP posology and administration frequency. Hence, further studies should be conducted
in the form of well-designed randomized controlled trials to clarify the long-term
results of aaPRP treatment in burn injury patients.
