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‘combination therapy’ where antibiotics of different classes are combined to cover the
suspected organism with more than one agent. The latter approach may be of benet
in patients with septic shock but is not recommended for most other serious infections. Infections associated with high levels of toxin mediated pathophysiology, such
as streptococcal toxic shock syndrome or necrotising soft tissue infections may benet from treatment with both a bactericidal and protein synthesis inhibiting antibiotic
(e.g. penicillin and clindamycin). In patients at risk of invasive Candida infection
consider empiric antifungal cover, generally echinocandins in critically ill patients.
Once the causative pathogen and it’s antimicrobial sensitivities are dened antibiotic therapy should be rened to the narrowest spectrum effective agent. If cultures are negative monitored de-escalation may be appropriate based on clinical
response. Data regarding de-escalation is scant but there are clear benets to avoiding unnecessarily prolonged antibiotic exposure for both society and the patient.
Unnecessarily prolonged antibiotic therapy promotes C difcile colitis, superinfection with multi-drug resistant organisms and is associated with increased mortality
[34]. Treatment with appropriate antibiotics for 7–10days appears adequate for
most serious infections complicated by sepsis or septic shock. Rapid clinical resolution and early effective source control may permit shorter courses (for instance surgically treated intra-abdominal sepsis and uncomplicated pyelonephritis). There
may be benet in longer courses when source control cannot be achieved, clinical
resolution is slow, immune deciency exists or in cases of S aureus bacteraemia or
fungal infection. Daily assessment for de-escalation of antibiotic therapy is effective
and may improve survival. Input from an infectious disease specialist is worthwhile.
As noted above, PCT measurement can be used to shorten duration of antibiotic
therapy in patients with resolving sepsis or support the decision to discontinue antibiotics when ongoing evidence for a presumptive diagnosis of sepsis is weak.
B. Reddi
17.7.3 Source Control
When septic shock arises from infection in a site amenable to source control the
time to intervention is a critical determinant of survival [68, 69]. Specically abscess
drainage, debridement of infected tissue, removal of an infected device or denitive
control of an ongoing source of microbial contamination should be undertaken as
soon as possible; in some cases haemodynamic stability cannot be achieved without
source control and prolonged efforts at medical stabilisation may be
counterproductive.
17.7.4 Corticosteroids
Septic shock appears to be associated with relative adrenal insufciency [22]. The
putative benets of corticosteroid supplementation are two-fold: (1) A generally
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anti-inammatory effect—corticosteroids suppress chemokine and cell adhesion
molecule expression, antigen presentation and lysosome degranulation, phospholipase A2 mediated production of arachidonic acid derivatives and pro-inammatory
cytokine production (e.g. TNFα, IL-1, IL-2, IL-8). Lymphocytic T-cells are shifted
from pro-inammatory Th1 to anti-inammatory Th2 phenotype [70]. (2)
Augmenting vasomotor tone—corticosteroids promote α1-adrenergic receptor sensitivity by increasing inositol trisphosphate (IP3) release and potentiating downstream sensitivity to protein kinase C.These effects are independent of changes in
plasma catecholamine levels, adrenergic receptor expression or ligand binding
afnity. Conversely, angiotensin II activity is augmented by increased angiotensinogen levels and increased receptor density. More generally, corticosteroids promote
vasomotor tone by inhibiting endothelial nitric oxide release, stimulating endothelin
release, and modulating vascular smooth muscle cell Na+ and Ca2+ handling [71].
Outcome data regarding corticosteroid therapy in septic shock is conicting and it
is unclear whether steroid therapy in septic shock is associated with a mortality
benet. Nevertheless, administering 200mg hydrocortisone daily to vasopressor
dependent, mechanically ventilated patients with septic shock appears to be safe
and associated with quicker resolution of shock [10, 72]. Evaluating adrenal function in septic shock (e.g. synacthen test, plasma cortisol assay) is difcult to interpret and not generally useful.
409
17.7.5 Adjunctive Therapies
Intensity of supportive therapies such as blood sugar control and dosing of renal
replacement therapies are now informed by randomised control trial data [73, 74].
However, data supporting more specic adjunctive therapies for sepsis and septic
shock have proven elusive. Strategies which enhance the activity of potentially benecial endogenous pathways (activated protein C [75], thrombomodulin, intravenous immunoglobulins, granulocyte colony stimulating factor,
anti-Enterobacteriaceae monoclonal antibody) or suppress activity of deleterious
pathways (TNFα, IL-1, NO, arachidonic acid derivatives, TLR-4) have been evaluated in patients with septic shock. They have not shown convincing outcome benet, and none are recommended for use in septic shock. Observational studies
indicated that HMG CoA reductase inhibitors (statins) were associated with
improved outcomes in sepsis, potentially through favourable modulation of the
immune, endothelial and coagulation systems. However, prospective studies have
not borne out this initial promise [76]. Blood purication techniques (such as haemoltration) are effective at removing inammatory mediators but do not appear to
improve outcome from septic shock and a recent randomised controlled study indicates that polymyxin B haemoperfusion does not benet patients with septic shock
[77]. Biologically, perhaps this is not surprising—inammatory and immune pathways have built in redundancy and mediators are pleiotropic. Targeting one mediator may not signicantly redene the immunological landscape and even if it does,
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B. Reddi
the effects may be unpredictable and dynamic. Furthermore, most of these adjunctive therapies, like steroids, are borne of the ‘maladaptive inammation’ paradigm
of sepsis and may be less rational in the context of subtler immune dysfunction.
17.8 Conclusion
Sepsis and septic shock are common and often fatal. Our understanding of the
pathophysiology is maturing but remains incomplete. We are beginning to appreciate the tensions between adaptive and maladaptive changes, excessive inammation
and immunoparesis, but have not yet identied specic therapies which can resolve
them. Patients are best served by a sound application of microbiological principles
and physiologically rational approach to supportive therapy.
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Further Reading
Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of
the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–8. https://doi.
org/10.1016/S1473-3099(13)70001-X.
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Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care
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Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, etal. The third inter-
national consensus denitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801–10.
https://doi.org/10.1001/jama.2016.0287.
Chapter 18
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Pathophysiology ofReperfusion Injury
PrueCowled andRobertFitridge
Key Learning Points
Ischaemia-Reperfusion Injury (IRI) is the paradoxical local and remote tissue
•
damage which occurs when perfusion is returned to ischaemic tissue.
• Tissue ischaemia occurs when perfusion is less than what is required to provide
tissues with adequate oxygen, glucose and other substances which are required for
normal cellular function. This results in anaerobic glycolysis which inhibits ATP
production and generates lactic acid. This results in tissue acidosis, failure of cel-
lular ATP-dependent pumps and efux of cellular potassium. A large number of
pro-inammatory genes and transcription factors are up-regulated during ischaemia.
•
When oxygen returns to ischaemic tissue, xanthine oxidase catalyses the conver-
sion of hypoxanthine to superoxide anions, which are subsequently converted to
reactive oxygen and nitrogen species (such as superoxide anion, hydrogen per-
oxide, hydroxyl radical, nitric oxide and peroxynitrite).
• Reactive oxygen species (ROS) cause lipid peroxidation of cellular membranes
and the generation of pro-inammatory eicosanoids. ROS also activate endothe-
lial cells which express adhesion molecules such as E-selectin, vascular cell
adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1),
endothelial-leukocyte adhesion molecule-1 (ELAM-1), plasminogen activator
inhibitor-1 (PAI-1), tissue factor and interleukin-8 (IL-8).
Eicosanoids are straight-chain polyunsaturated fatty acids that are derived from
•
arachidonic acid and include prostaglandins, thromboxanes and leukotrienes.
They are signalling molecules that modulate inammation, immune responses
and tissue blood ow.
P. Cowled · R. Fitridge (*)
Discipline of Surgery, The University of Adelaide, The Queen Elizabeth Hospital,
Woodville South, SA, Australia
e-mail: prue.cowled@adelaide.edu.au; robert.tridge@adelaide.edu.au
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_18
415© Springer Nature Switzerland AG 2020
416
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• Nitric oxide is synthesised from L-arginine by nitric oxide synthases (NOS).
There is an initial surge in NO levels in early ischaemia (rst 15min) due to tran-
sient activation of endothelial NOS (eNOS). During early reperfusion, the endo-
thelial damage results in loss of eNOS function and a fall in NO production. This
predisposes to vasoconstriction and potentially exacerbation of tissue ischaemia.
• Endothelins are potent vasoconstrictors which are produced by the vascular
endothelium and are elevated in IRI.
• Hypoxia and IRI induce numerous cytokines such as tumour necrosis factor-α,
interleukins-1, -6 and -8 and platelet activating factor, which are released sys-
temically and play a key role in the development of systemic inammatory
response syndrome and multi-system organ failure associated with IRI.
• Neutrophils are activated during IRI and play a key role in tissue damage.
Activated neutrophils generate ROS and a number of proteases, such as matrix
metalloproteinases (MMPs).
• Selectins are transmembrane molecules expressed by activated neutrophils, acti-
vated endothelial cells and platelets. Selectins mediate the initial neutrophil-
endothelial interaction/adhesion. Integrins and members of the immunoglobulin
supergene family (e.g. ICAM-1, VCAM-1, platelet-endothelial cell adhesion
molecule-1) mediate rm adhesion of activated neutrophils to the endothelium
and allow their extravasation into the tissues. The ROS and proteases generated
by inltrating neutrophils contribute to tissue damage in IRI.
• Complement activation contributes to local and systemic IRI.
• Toll-like receptors (TLR) are proteins involved in the innate immune system.
TLR signalling is a key mediator of inammation during IRI.
• Matrix metalloproteinases (MMPs) are enzymes which can degrade extracellular
matrix. Elevated MMP-2 and -9 have been detected in cerebral, skeletal muscle
and pulmonary IRI, resulting in destruction of basement membrane collagen and
laminin.
• The no-reow phenomenon is the failure of microvascular perfusion following
reperfusion due to plugging of post-capillary venules by activated leukocytes and
increasing permeability of endothelium resulting in exudation of uid and pro-
teins with subsequent increase in interstitial pressure.
•
The complexity of the pathophysiology of IRI has resulted in the failure of thera-
peutic interventions to have been adopted into clinical practice. Ischaemic pre-
conditioning holds theoretical promise in reducing IRI in vascular surgery but
further larger trials are needed. Ischaemic post-conditioning and the effects of
volatile anaesthetic agents on ameliorating the severity of IRI also require further
investigation.
P. Cowled and R. Fitridge
18.1 Introduction
Ischaemia-Reperfusion Injury (IRI) is dened as the paradoxical exacerbation of
cellular dysfunction and death, following restoration of blood ow to previously
ischaemic tissues. Reestablishment of blood ow is essential to salvage ischaemic
18 Pathophysiology ofReperfusion Injury
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tissues, however reperfusion itself paradoxically causes further damage, threatening
function and viability of the organ. IRI occurs in a wide range of organs including
the heart, lung, kidney, gut, skeletal muscle and brain and may involve not only the
ischaemic organ itself but may also induce systemic damage to distant organs,
potentially leading to multi-system organ failure. Reperfusion injury is a multifactorial process resulting in extensive tissue destruction. The aim of this review is
to summarise these molecular and cellular mechanisms and thus provide an insight
into possible windows for effective therapeutic intervention.
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18.2 Ischaemia
18.2.1 ATP andMitochondrial Function
Ischaemia occurs when the blood supply is less than the demand required for normal function, resulting in deciencies in oxygen, glucose and other substances
required for metabolism. Derangements in metabolic function begin during this
ischaemic phase. Initially, glycogen breakdown by mitochondrial anaerobic glycolysis produces two molecules of adenosine triphosphate (ATP) along with lactic
acid, resulting in a decrease in tissue pH, which then acts by negative feedback to
inhibit further ATP production (Fig.18.1). ATP is then sequentially broken down
into adenosine diphosphate (ADP), adenosine monophosphate (AMP) and inosine
monophosphate (IMP) and then further into adenosine, inosine, hypoxanthine and
xanthine (Fig.18.2, upper panel).
At the cellular level, a lack of ATP production causes ATP-dependent ionic
pumps, including the Na+/K+ and Ca2+ pumps, to fail and the transmembrane ionic
gradients are lost. Consequently, cytosolic sodium content rises, drawing with it, a
volume of water to attempt to maintain the osmotic equilibrium and resulting in
hydroponic swelling of the cells. To maintain the ionic balance, potassium ions
escape from the cell into the interstitial space (reviewed in [1]). Calcium is released
from the mitochondria into the cytoplasm and into extracellular spaces, thereby
activating mitochondrial calcium-dependent cytosolic proteases including calpain,
which then converts the cellular enzyme xanthine dehydrogenase to xanthine oxidase (Fig.18.2, upper panel). Phospholipases are also activated during ischaemia,
degrading membrane lipids and increasing the levels of circulating fatty acids.
18.2.2 Gene Expression During Ischaemia
As well as metabolic derangements, ischaemia induces expression of a large number of genes, which play a major role in the tissue’s response to ischaemic damage.
An RNA expression microarray analysis, using mouse soleus muscle rendered ischaemic by femoral artery ligation, found that expression of 962 genes was induced
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