Mengapa terjadi peningkatan permeabilitas vaskular pada pasien luka bakar?

Jawab :

Jadi, resusitasi luka bakar ada 2 fase, yaitu fase hypodinamic dan fase hiperdinamik. Terjaidnya
peningkatan permeabilitas vaskular terjadi pada fase hypodinamic. Fase hipodinamik terjadi selama
kurang lebih 24 hingga 72 jam pertama.

Peningkatan permeabilitas mikrovaskuler terjadi karena

1. Cedera vaskular langsung

Jejas pada endotel pembuluh darah akibat luka bakar menyebabkan kebocoran vaskular dengan
cara nekrosis dan lepasnya sel endotel. Umumnya memang kebocoran terjadi segera setelah
cedera dan berlangsung beberapa jam atau hari hingga terjadi thrombosis pada pembuluh darah
yang rusak atau terjadi pemulihan.
2. Melalui pelepasan mediator inflamasi.

Peningkatan permeabilitas pembuluh darah menyebabkan pergeseran cairan intravaskular dan

protein plasma ke ruang interstisial

3. Apa yg dimaksud ekpansi volume?

Jawab :

kspansi volume plasma (plasma volume expansion=PVE) yang konvensional setelah suatu infus
cairan mengatakan bahwa cairan yang tertahan (cairan masuk dikurangi dengan cairan keluar)
didistribusikan ke ruang-ruang cairan tubuh berdasarkan pada volume ruang cairan fisiologis.

4. Tekanan osmotic adalah?

Jawab :

tekanan osmotik adalah tekanan yang diperlukan untuk menghentikan osmosis, yaitu
gerakan molekul pelarut melewati membran semipermeabel ke larutan yang lebih pekat.

5. Apa itu tekanan onkotik?

Jawab:
Tekanan onkotik adalah suatu bentuk tekanan osmotik yang dipengaruhi oleh albumin dalam
plasma pembuluh darah, yang cenderung menarik air ke sistem sirkulasi darah.
6. Apa beda koloid dan kristaloid?
Jawab:
Larutan koloid adalah suspensi molekul dalam larutan pembawa yang relatif tidak
mampu melintasi membran kapiler semipermeabel yang sehat karena berat molekul
molekul. Crystalloid adalah larutan ion yang bebas permeabel tetapi mengandung
konsentrasi natrium dan klorida yang menentukan tonisitas cairan

7. Mengapa resusitasi cairan pada luka bakar di 24 jam pertama menggunakan cairan
kristaloid?
Jawab:
Resusitasi awal didasarkan pada kristaloid.5 6 Walaupun telah dibuktikan bahwa larutan
ini memiliki efek ekspansi volume yang lebih kecil dari koloid,45 . Efek ekspansi volume
cairan koloid lebih besar daripada cairan kristaloid artinya koloid cenderung untuk tetap
berada di dalam kompartemen intravaskuler karena koloid memiliki berat molekul tinggi
dan mengandung partikel onkotik dan karenanya menghasilkan tekanan onkotik. Namun,
pada luka bakar terjadi peningkatan permeabilitas kapiler yang terjadi selama 24 jam
pertama, walaupun memiliki berat molekul yang besar, koloid tetap akan lolos ke ruang
ekstravaskular, mengerahkan efek onkotik, dan menyebabkan augmentasi paradoksikal
dari apa yang biasa disebut ruang ketiga (third space) yaitu ruang tertentu dimana tidak
mudah terjadi pertukaran dengan ECF ditambah lagi karena berat molekul koloid besar,
koloid tiak bisa masuk kembali ke ruang intravascular. Apabila pasien luka bakar
diberikan cairan koloid, maka cairan akan keluar dari intravascular (ke ruang ketiga)
namun cairan tersebut tidak bisa masuk kembali ke ECF (termasuk intravascular). Efek
jangka panjang dari tertumpuknya cairan di ruang ketiga ini yaitu ……….. ( yang
gangguan ginjal yg kata dr.ferdi).

8. Apa itu ruang ketiga?

Terkumpulnya cairan di dalam ruang non ECF dan non-ICF disebut penempatan pada
ruang ketiga. Yang dimaksud adalah distribusi cairan yang hilang ke ruang tertentu
dimana tidak mudah terjadi pertukaran dengan ECF. Pada prinsipnya cairan menjadi
terperangkap dan tidak dapat dipakai oleh tubuh. Penumpukan volume cairan yang
 cepat dan banyak pada ruang-ruang seperti itu berasal dari volume ECF sehingga dapat
mengurangi volume sirkulasi darah efektif.

9. Glycocalyx itu apa?

Jawab:
Glikokaliks endotel adalah polimer protein dan polisakarida yang menutupi permukaan
apikal (luminal) dari endotelium mikrovaskular.

Fungsi glycocalix :

1. as the endothelial gatekeeper.

Located between the blood stream and the endothelium, the endothelial glycocalyx is
an important determinant of vascular permeability [35, 130]. It is able to limit access of certain
molecules to the endothelial cell membrane,

2. as mechanotransducer
The endothelium is exposed to mechanical forces induced by blood flow. It has long
been recognized that these forces, in particular, shear stress, determine endothelial cell
morphology and function [16, 18]. Endothelial cells exposed to shear stress produce nitric oxide
(NO) [96], which is an important determinant of vascular tone. However, the molecule(s)
responsible for the translation of biomechanical forces into biochemical signals
(mechanotransduction) have not been identified as yet. Recently, the glycocalyx has been added
to the list of possible candidates.
Read : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042904/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1915585/
 10. Burn oedem
Jawab :

Chapter 7Pathophysiology and Clinical

Relevance
Go to:

BURN EDEMA
Thermal injury affects more than 2 million Americans each year. Clinically, burns are evaluated
based on wound depth (degree) and coverage area (% of total body surface area, TBSA). A first-
degree burn causes redness and swelling in the outmost layers of skin (epidermis). A second-
degree burn involves redness, swelling, and blistering with damage extended beneath the
epidermis to deeper layers of skin (dermis). A third-degree burn, also called a full-thickness
burn, destroys the entire depth of skin and may extend to the underlying fat, muscle, or bone,
causing significant scarring. Major (or severe) burns are defined as first- or second-degree burns
covering >25% TBSA in adults (>20% in children), or a third-degree burn covering >10% BSA.

Despite the remarkable improvement in critical care and wound management, systemic
complications remain a major cause of mortality and morbidity in patients with severe burns
even after successful initial resuscitation. Of great concern is the development of massive edema
accompanied by a systemic inflammatory response syndrome (SIRS) that affects multiple organs
and tissues. As a cardinal component of systemic inflammation, microvascular leak occurs not
only locally at the burn wound, but also in distant tissues remote from the wound [27]. The leak
response peaks within the first 1–6 hours and starts to resolve by 6–12 hours [58, 70, 109, 284,
352]. Loss of plasma fluid is the major cause of circulatory (hypovolemic) shock. Accumulation
of protein-rich fluid in tissues impedes the local microcirculation and blood–tissue exchange,
resulting in tissue malperfusion and hypoxia [8, 105, 109, 196, 434]. Intensive fluid therapy
helps maintain the circulatory stability of patients during the resuscitation period; however,
without effective approaches to stop vascular leakage, excessive fluid administration exacerbates
edema contributing to adult respiratory distress syndrome (ARDS), abdominal compartment
syndrome, and, in worse cases, multiple organ failure [27, 105, 169, 284].

Hypotheses that explain the onset and progress of plasma accumulation in tissues include
increased fluid filtration pressure (due to vasodilation), blockage of lymphatic clearance, and
increased interstitial osmotic activity [26, 109, 236, 284, 352]. With respect to the latter, it is
believed that the thermal effect on tissues causes breakdown of the scaffolding matrix (collagen,
collagen, hyaluronic acid, etc.), leading to increased interstitial compliance and accumulation of
matrix fragments in the extravascular space. These small fragments serve as osmotically active
molecules that produce a “sucking” force for the outward flux of plasma fluid. Based on this
theory, clinicians formulate fluid therapies for burn patients centering on volume
supplementation while correcting the imbalance of the Starling forces. A variety of resuscitation
fluids have been developed, including hypertonic saline and fluids containing colloids or
macromolecules (albumin, dextran, and PEG). Although these solutions seem to be highly
effective in ameliorating or delaying the progress of burn edema in animals, their beneficial
effects and efficacy in human patients are not definitive. Currently, hypertonic saline and colloid
fluids are under extensive clinical evaluation for long-term outcomes in trauma patients and for
identifying their mechanisms of action at the cellular and molecular level.

Microvascular hyperpermeability has thus far been considered the most important mechanism of
edema, especially in tissues remote from the burn wound site [91, 142, 410]. Accordingly, an
array of permeability-increasing mediators, including histamine, prostaglandins, and cytokines,
has been identified in the circulation of burn patients [26, 27, 158]. In particular, tissue injury-
coupled activation of complements triggers mast cell degranulation. Mast cells are located in
proximity to blood vessels in all tissues. As the major granule content of mast cells, histamine is
released and acts on the endothelium, causing junction opening and increased paracellular
permeability (molecular details described in the previous chapters). Meanwhile, multiple cascade
systems in human plasma can be triggered by thermal injury, including the arachidonic acid
cascades (producing prostaglandins), the kallikrein cascade (producing bradykinin and plasmin),
the complement cascades (activating C3 and C5a), and the coagulation/fibrinolytic cascades
(forming fibrin clots and fibrin degradation products). The majority of these products are capable
of increasing microvascular permeability. In addition, cytotoxic metabolites and apoptotic
mediators produced by activated leukocytes and macrophages (such as oxidants and proteases)
contribute to the injurious process [398, 476, 505]. More details regarding the role of leukocytes
in microvascular barrier injury are provided in the following section (ischemia–reperfusion
injury).

However, despite the progress in identifying the biological sources and chemical natures of
edematous factors, attempts to block individual mediators as therapeutic means for treating burn
edema have met with limited success. For example, a clinical trial with leukocyte antiadhesion
therapy was discontinued due to high mortality [90, 157]. Histamine antagonists have been used
in burn patients but their therapeutic significance is questioned along with concerns about their
adverse hemodynamic effects [27]. Prostaglandin inhibitors fail to improve microvascular
function while delaying wound healing and causing perioperative bleeding [27, 83, 323], and
COX-2 inhibitors cause cardiovascular distablization while showing minimal protection in
immunocompetent subjects [136, 323]. On the other hand, steroids are efficacious as anti-
inflammatory therapeutics, but are used restrictively as they suppress the host defense and
increase the risk of infection and bone degeneration [27]. Overall, many of the anti-inflammatory
drugs exert unwanted effects, and the complex interactions among multiple inflammatory
pathways underscore the limited effectiveness of individual antagonists [83, 157, 168, 323].
These problems signal the need for development of alternative clinical strategies. Interventions
or therapeutic agents directly targeting the end-point cellular processes that ultimately open the
microvascular barrier may lead to a new direction in trauma research.

MLCK is a common endpoint effector for multiple signaling pathways triggered by circulating
inflammatory factors in response to trauma. Recent molecular studies in animal models of burn
injury support the therapeutic potential of MLCK inhibition in attenuating microvascular
leakage. Treatment with ML-7 significantly attenuates burn-induced splanchnic microvascular
hyperpermeability in a dose-dependent manner [205]. The construction of MLCK-210 knockout
mice [471] has enabled in vivo testing of the nmMLCK-mediated microvascular barrier response
to stress or injury [285]. Compared with wild-type mice which show increased albumin transflux
and hydraulic conductivity in intestinal and mesenteric microvessels after severe burns, MLCK-
210 knockout mice demonstrate attenuated microvascular leak and improved survival after
severe burns [381]. In contrast, endothelial-specific overexpression of MLCK2 in transgenic
mice shows enhanced plasma protein leakage into lung tissue during sepsis or injury, suggesting
that individual nmMLCK isoforms mediate endothelial hyperpermeability in vivo [313].
Currently, research efforts are being devoted to the development and testing of MLCK isoform-
specific inhibitors as potential therapies for microvascular injury during trauma or sepsis.

11. Apa kompliksi jangka panjang dan jangka pendek dari luka bakar?
Jawab: