Aetiology of nosocomial infection in ICU:

Pneumonia: VAP or HAP

Central line associated bacteraemia
UTI due to indwelling catheters
Sinusitis due to nasogastric tubes
Acalculous cholecystitis due to parenteral nutrition
Pressure area infections
Meningitis or ventriculitis due to EVD infection
C. difficile infections due to broad -spectrum antibiotic use
Surgical site infections
Clinical manifestations

Broadly speakin g, these depend on where the infection is.

Fever
Inflammatory marker elevation
Sh ock and metabolic acidosis
Purulent discharge (pulmonary, urinary, or nasal)
Positive CSF gram stain and culture, decreased level of consciousness
Preventative measures

Non-specific m easures

Scrupulous h andwashing
Barrier precautions, gloves gown s and m asks
Surveillan ce for MROs
Isolation precautions
Specific measures

Regular oral hygiene

Regular pressure area care
Minimisation of the duration of ventilation
Preventative strategies for VAP (eg. upright positioning)
Preventative strategies for central lin e contamination
Early removal of central lines
Rationalisation of antibiotics to prevent C.difficile infection
Control of hyperglycaemia
Rationalisation of immunosuppressive therapies
Perioperative antibiotics to prevent wound infection in high -risk patients
Critically evaluate the role of fluid resuscitation in critically ill patients with sepsis.
Introduction:

Fluid resuscitation has been the traditional starting point in the resuscitation of sepsis
The choice of fluids and the required volume remain topics of debate
Rationale:
Fluid resuscitation maintains intravascular volume and organ perfusion pressure
Fluid resuscitation maintains preload, ensuring an adequate cardiac output
Fluid resuscitation improves microvascular perfusion and thus tissue oxygen delivery
H aemodilution decreases blood viscosity, which may also improve microcirculatory flow
Evidence:

Recent evidence regarding the ch oice of fluids (SAFE, ALBIOS) h as demonstrated the non-
inferiority of crystalloid as con1pared to colloid in terms of n1ortality; h owever,
h aemodynamic goals appear to be achieved fas ter with human albumin.
There is some argument (on the basis of subgroup analysis) that albumin use may be
associated with increased survival in sepsis.
1here is a strong argument against fluid over-resuscitation, and it is known that every 1 L of
positive fluid balance at day 3 after admission is associated with an increase in mortality.
Summary

Fluid resuscitation is an important part of the resuscitation of sepsis

It should be guided by dynamic markers of fluid responsiveness
It should be guided by haemodynamic goals and surrogate markers of tissue perfusion
(e g.lactate)
Its use should be curtailed to prevent excessively positive fluid balance
21.1 -1his looks like a hyperdynamic circulation with decreased peripheral resistance. You can even
calculate SVRI using the usual equation:

SVRI =([MAP-RAP] X 79.9) I CI

Thus, the SVRI is ([59-5] x 79.9 )/ 3.8

= 1135 dynes xsec/cm 5;M2

That is pretty low- the normal range is 1800-2400.

21.2 Why would the peripheral resistance be so low?

Septic shock
Anaphyactic shock
Neurogenic (spinal) shock
Vasodilation due to SIRS following a global hypoxic/ischaemic injury
SIRS due to cardiopulmonry bypass
Vasodilation due to pharmacological agents (eg. nitrates)
Vasodilation due to severe liver disease
21.3 Mechanisms of vasodilation in sepsis:

Nitric oxide synthase induction by cytokines and endotoxin

Direct vascular smooth muscle response to acidosis and hypoxia - this is mediated by
theactivation of ATP-sensitive K+ channels, which which hyperpolarise the smooth muscle
cell membranes, preventing contraction and producing vasoplegia.
Inflammatory mediators produced by activated leucocytes
Vasodilatory mediators (eg. histamine bradykinin and serotonin) produced by leukocytes and
platelets
Relative vasopressin deficiency
Relative adrenal insufficiency, resulting in peripheral catecholamine insensitivity
Acidosis, resulting in peripheral catecholamine insensitivity
Critically evaluate the role of vasopressin in septic shock.
 Introduction I definition:
o Vasopressin is an important adjunct to the management of septic shock, and works
synergistically with catecholan1ine vasopressors.
 Rationale:
o Vasopressin acts on Vl and V2 receptors, of which the Vl receptors are responsible for
its vasoconstrictor properties.
o Activation of these receptors leads to vasoconstriction which is synergistic with the
vasoconstriction form catecholamine vasopressors, thus decreasing catecholamine
requirements.
 .L

o Vasopressin does not have proarrhythmic properties of catecholamine agents, and may
be used as a catecholamine-sparing agent
o Vasopressin receptor sensitivity is unchanged in the setting of severe acidosis, while
catecholamine receptors lose their sensitivity.
o There is also a concept of "relative vasopressin insufficiency" which suggests that in
states of severe shock the endogenous secretion of vasopressin is inadequate, and
vasopressin needs to be supplemented in order to maintain an adequate vasopressor
response.
 Evidence: what the recent trials say
o The VASST trial had demonstrated that vasopressin alone is not inferior to noradrenaline
as a vasopressor in septic shock
 .L .L

Advantages
o Decreased catecholamine requirements
o Maintained activity in severe acidosis
o Non-arrhythmogenic
o Promotes the retention of resuscitation fluid
 Disadvantages
o Causes splanchnic vasoconstriction, which may pron1ote anastomotic breakdown and
worsening of gut ischaemia.
o Causes increased peripheral vasoconstriction, which may result in ischaemia of the
extremities
o May cause cardiac ischaemia due to coronary vasoconstriction
o Requires central venous access to administer
 Own practice:
o Vasopressin is useful as an adjunct in severe shock states which feature low peripheral
vascular resistance, and should be added to catech olamine vasopressors in situations of
increased catech olamine requirements or catech olamine resistance.
 a) What is the endothelial glycocalyx? Outline its potential importance in sepsis.

1he glycocalyx is a thin (500-l OOOnm) hydrated gel-like layer on th e luminal surface of the
vascular endothelium
It is composed of a vast variety of macromolecules, including glycoproteins, polysacch arides,
proteoglycans, glycosaminoglycans, plasma proteins, enzymes and enzyme inhibitors, growth
factors, cytokines, amino acids, cations and water.
Glycocalyx degradation may be resposible for much of the organ damaged observed in sepsis.
Con centration of glycocalyx compon ents shed into the bloodstrean1 correlates with sepsis
severity .
b) Name factors that can disrupt the endothelial surface layer (ESL).
o Hyperglycaemia
Any path ological process that is known to cause atheroma formation: o Hyperlipidaemia
o Smoking
Inflammation, mediated by TNFa (this is prevented by hydrocortisone)
Ischaemia-reperfusion injury (which h alts the endothelial synth esis of glycosaminoglycan
Hypervolemia (mediated by actions of th e ANP)
Hydroxyethyl starch ( in same study that investigated the effects of hypervolemia)
Major vascular surgery (seems like a consequence of bypass and isch aemia/reperfusion)
c) What are the effects of glycocalyx disruption?

Local hypercoagulability
Global autoheparinisation (especially during trauma)
Increased capillary pern1eability
o Tissue and organ oedema
o Impaired microcirculatory oxygen distribution
o Loss of vascular responsiveness

Increased platelet aggregation, leading to microvascular thrombosis and DIC

Increased leucocyte-endothelium interaction, leading to inflammation
 Beta-lactams can be either dose-adjusted or interval-adjusted
Carba2enems can be either dose-adjusted or interval-adj_u_s_te_d_ _ _ _ _ _ _ _ _ __
An1inog!ycosides kee2 the san1e dose, and are interval-adjusted (with n1onitoring_ of dru
levels)
Fluoroquinolones kee the san1e dose, and are interval-adjusted (with n1onitoring of the QT
interval)
GlycopeRtides kee2 the san1e dose, and are interval-adjusted (with n1onitoring_ of drug_ levels)
The risk factors for C.difficile infection are discussed here, in a NEJM article.

Where did the college answer get its evidence from, you ask?

Broad spectrum antibiotics in particular clindamycin, quinolones, amoxycillin, cephalosporins

Immunosuppressive therapy /Cytotoxic chemotherapy
Gastric acid suppression
Age> 65
Prolonged hospitalisation
Renal impairment
Diagnostic features:

Abdominal pain
Loose stools
History of broad spectrurn antibiotics, particularly Clindamycin
Characteristic "thurnbP.rintinK' of bowel on plan Xrays
Inflarned appearance of bowel on CT
Direct confirmation ofi seudon1en1branes on colonoscOP.Y
C. difficile toxin A orB on stool PCR
Toxic n1egacolon
Perforation and pneumoperitoneum
Fever> 38
Renal failure
As for diagnosis of C.difficile, the current recommendations are:

PCR is better than toxin A orB identification

You should only test loose stools
You should not re-test
Markers of "severe" enterocolitis, which n1eans the sort that ends up either killing you or results in a
colectomy, are deliniated in this retrospective study. They are as follows:

age > 70 years

maximum leukocyte count >20,000 cells/mL
minimum albumin level <25 g/L
maximum creatinine level >200 mcg/L
small bowel obstruction or ileus
CT evidence of colorectal inflammation

To this list, another study adds more markers of severity:

Fever (>38.0)
Abdon1inal distension
Briefly outline the difficulties encountered in the clinical and
laboratory diagnosis of se sis in the critical care unit.
Clinical criteria for SIRS have oor s ecifici for se sis

Not all se2tic patients are febrile or hypothermic. Many are normothermic.
Tachycardia can represent hypovolen1ia, anxiety, pain , or in otrope effect.
Tachy noea may represent anxiety, Rain or ase2tic metabolic acidosis
Some patient groups will not be able to manifest clinical features of SIRS:
o Malnourished 2atients
o Irnrnunocornprornised
o 1herapeutically cooled
o Elderly 2atients
o Hy2othyroid patients
Infectious an d non-infectious causes of SIRS may co-exist
!Infectious source may be unclear
1he patient is sedated and cannot 2artic_!Rate in history-taking.
There are no g_eneric features of 'infection' to look for.
S2ecific features of infection rna be obscured by other clinical finding_s __
Criteria for the diagnosis of an infectious source are fre uently not available (eg. central line
associated bacteraemia, ventilator-associated pneumonia, etc).
Clinical features of specific syndromes may be shared by non-infectious pathology (eg.
purpura fulminans)
!The laboratory markers of sepsis are non-specific

All biochemical n1arkers of se sis can becom e elevated due to non-infectious causes.
Serology tests and PCR studies rnay not be or anisrn-sP.ecific or n1ay require convalescent
sam2les.
Microbiology is unreliable, becau se:
o Sample may be difficult to obtain
o Organism may be difficult to culture (eg. Treponema pallidum)
o Sample may be sterilised by antibiotic therapy
o A positive sample culture may represent colonisation rather than infection .
o Cultures take time to develop, whereas sepsis evolves rapidly - empiric therapy must be
commen ced lon g before microbiology is available.
13.2 List an example of each of the three n1ain classes of systernic antifung_al ag_ents.

Polyene$ e.g. Amphotericin B

Azoles e.g. Fluconazole
Echinocandins e.g. caspofungin, andulafungin, micafungin
As for the antifungal drugs, in brief summary:
Polyenes like an1photericin and nystati 1 weaken fun gal cell walls by bin ding to ergosterol.
Azoles like fluconazole and voriconazole prevent the synthesis of ergosterol fron1 lanosterol
by inhibiting lanosterol 14 a -demethylase.
Echinocandins like cas ofun in inhibit fungal cell wall synthesis by blocking the synthesis of
glucan by 1 , 3 -~ glucan synthase.