Successfully reported this slideshow.
You’ve unlocked unlimited downloads on SlideShare!
Medicine in Mind Maps
Medical Science made incredibly simple
[created by Paul
- CXR identifies haemothorax, pneumothorax and pulmonary contusion
- AP pelvis can confirm presence of significant pelvic fracture
- lateral c-spine can identify non-survivable neck injury
(i) Airway(ability of air to pass unobstructed to the lungs):
critical findings include:
- obstruction of the airway due to direct injury, oedema, foreign body or inability
to protect the airway because of depressed level of consciousnesss
key treatment is:
- establishment of airway
(ii) Breathing (ability to ventilate and oxygenate):
key clinical findings are:
- absence of spontaneous ventilation, absent or asymmetrical breath sounds, dyspnoea
hyperresonance, dullness, gross chest wall instability or defects that compromise ventilation
key conditions to identify are:
- pneumothorax, endotracheal tube malposition, tension
pneumothorax, haemothorax, sucking chest wounds, flail chest
key treatment is:
- chest tube
key clinical findings are:
- collapsed or distended neck veins, signs or tamponade, external sites of haemorrhage
key conditions identified are:
- hypovolaemia, cardiac tamponade, external haemorrhage
key treatment is:
- iv access, fluid resuscitation, compression of sites of bleeding
key clinical conditions are:
- decreased level of consciousness, pupillary assymetry, gross weakness
key conditions identified are:
- serious head and spinal cord injury
key treatment is:
- definitive airway if indicated, emergency treatment of raised icp
(v) Exposure and control of immediate environment:
- expose patient and prevent hypothermia
- continues throughout primary and secondary survey and until treatments are complete
- fluids are required to sustain intravascular volume, tissue and organ perfusion and urine output
- administer blood for hypovolaemia that is unresponsive to crystalloid boluses
- end points are normal vital signs, absence of blood loss, adequate urine output and no evidence of end
organ dysfunction; blood lactate and base deficit on an ABG may be helpful in patients who are severely injured
several monitoring and diagnostic adjuncts occur in concert with the primary survey:
(i) ECG and ventilatory monitoring and continous pulse oximetry
(ii) decompress stomach with NG or OG tube once airway is secured
(iii) insert a foley cather during resuscitation phase (foley catheter placement is contraindicated
if urethral injury is evident as identified by blood at the meatus, ecchymosis or scrotum or
labium majora or high riding prostate - retrograde urethrogram is required for these patients)
Secondary survey of abdominal trauma:
- examine for the presence of external signs of injury noting patterns of abrasion and/or ecchymotic areas
- lap belt bruising is positively correlated with rupture of the small intestine and increased incidence of other
intraabdominal injury (20-30% of patients with lap-belt marks have associated mesenteric or intestinal injuries)
- bradycardia may indicate free intraperitoneal blood
- Cullen sign (periumbillical ecchymosis) may indicate retroperitoneal
haemorrhage; however, this usually takes hours to develop
- flank bruising and swelling may raise suspicion for retroperitoneal injury
- inspect genitals and peritoneum
- fullness may indicate haemorrhage
- crepitation of lower rib cage may indicate hepatic or splenic injury
- rectal and vaginal examination identify potential bleeding and injury
- signs of peritonitis soon after injury suggest leakage of intestinal contents;
peritonitis due to intra-abdominal haemorrhage may take several hours to develop
- used to identify free fluid in the peritoneal cavity
- FAST has a sensitivity of 70-95%
- involves directing to ultrasound probe in four regions:
(i) the subxipoid location to determine whether there is fluid in the pericardial
space & to make a rough assessment of contractility & filling state
(ii) the right upper quadrant
(iii) the splenorenal recess
(iv) the pelvis
- problems with FAST:
(i) operator dependent
(ii) false negative rate in children is high
(iii) technically more difficult with obesity & sc empysema
- is the diagnostic modality of choice for haemodynamically stable patients
- the major reason not to obtain a CT scan is haemodynamic instability
- allows haemoperitoneum & its source to be identified & allows specific injuries to be graded
- CT also permits evaluation of retroperitoneal structures including the kidneys, major blood vessels & bony pelvis
- the majority of blunt solid organ injuries are now managed non-operatively in trauma centres; however, a
blush of intravenous contrast agent indicates active extravasation from a bleeding vessel and is strong predictor
of failure of non-operative management
- problems with CT scanning are:
(i) the need to transfer the patient to radiology
(ii) the time associated with transfer and scanning
(iii) risks associated with intravenous contrast agents
(iv) the fact hollow viscus, diaphragmatic & pancreatic injuries are frequently missed on initial scanning
abdominal trauma consists of blunt and penetrating trauma
Penetrating abdominal trauma:
- most commonly injured organs with stab wounds are small intestine, liver and colon
- only one third of abdominal stab wounds penetrate the peritoneum & only 50% of
these require surgical intervention
- 85% of abdominal wall gun shot wounds penetrate the peritoneum & 95% of these
require a surgical procedure for correction
Blunt abdominal trauma
- spleen and liver are the most commonly injured organs; small and large intestines are the next most commonly injured
- has an accuracy of 98% for detection of haemoperitoneum but does not determine source
- generally performed in patients too unstable for CT
- involves performing a minilaparotomy with placement of a lavage catheter into the periotoneal
cavity directed towards the pelvis
- the return of gross blood is a positive result
- if DPL is grossly negative then 1L of warmed saline is instilled into the the abdominal cavity &
then drained back into the intravenous fluid bag by gravity. The effluent lavage is sent to the
laboratory for analysis.
- laboratory criteria for a positive DPL in blunt trauma are:
(i) >100000 RBCs/mm3
(ii) >500 WBC/mm3
(iii) presence of food particles
(iv) presence of bile
(v) presence of bacteria
- problems with DPL:
(i) an invasive procedure
(ii) 1/4 of patients with a positive DPL will have a non-therapeutic laparotomy
(iii) 5% false negative rate with retroperitoneal, hollow viscus or diaphragm injuries
- ongoing haemorrhage is the most likely cause of persistent or recurrent haemodynamic instability
- initial goal is not to diagnose specific abdominal organ injury but rather to determine wheter there are
signs & symptoms that indicate a need for immediate laparotomy
30% of patients with lumbar Chance fracture have associated bowel or mesenteric injuries
Normally, expiratory flow returns to the baseline prior to the next breath.
In the event that the expiratory flow does not return to the zero line and
the subsequent inspiration begins below the baseline, auto-PEEP or air
trapping is present.
The presence of auto-PEEP or air trapping may result from:
a. Inadequate expiratory time
b. Too high a respiratory rate
c. Long Inspiratory Time
d. Prolonged exhalation due to bronchoconstriction.
- The classic sign, known as "Beak Effect" or "Duckbill" shows an
increase in airway pressure without any appreciable increase in volume.
baseline of the pressure-time waveform shows slight up and down
movements with heartbeat; these may initiate triggering of synchronised
- demonstrates normal PIP , Pplat , PTA (transairway pressure), and Ti (inspiratory time).
- A significant increase in the PTA is associated with increased in airway resistance.
- the inspiratory time is shorter than normal, indicating a higher inspiratory gas flow rate.
Decreased Lung Compliance:
- An increase in the plateau pressure and a corresponding increase in the PIP is consistent
with decreased lung compliance.
- inadequate inspiratory flow rate on the pressure time waveform
leads to a 'scooped out' appearance to the synchronised breaths
there is less volume expired than inspired
baseline of the pressure time waveform drifts downwards
- This is also referred to as classic RTA or distal RTA.
- The problem here is an inability to maximally acidify the urine. Typically
urine pH remains > 5.5 despite severe acidaemia ([HCO3] < 15 mmol/l).
- Some patients with less severe acidosis require acid loading tests
(eg with NH4Cl) to assist in the diagnosis. If the acid load drops the
plasma [HCO3] but the urine pH remains > 5.5, this establishes the diagnosis.
General Classification of Causes of type 1 RTA
(ii) Autoimminue diseases (eg Sjogren's syndrome, SLE, thyroiditis)
(iii) Disorders which cause nephrocalcinosis (eg primary hyperparathyroidism, vitamin D intoxication)
(iv) Drugs or toxins (eg amphotericin B, toluene inhalation)
(v) Miscellaneous - other renal disorders (eg obstructive uropathy)
Pathophysiological Mechanisms in Reduced H+ Secretion in Distal Tubule
(i) "Weak pump"
- Inability for H+ pump to pump against a high H+ gradient
(ii) "Leaky membrane"
- Back-diffusion of H+ [eg This occurs in RTA due amphotericin B]
(iii) "Low pump capacity"
- Insufficient distal H+ pumping capacity due to tubular damage.
- Typical findings are an inappropriately high urine pH (usually > 5.5), low acid secretion
and urinary bicarbonate excretion despite severe acidosis. Renal sodium wasting is
common and results in depletion of ECF volume and secondary hyperaldosteronism with
increased loss of K+ in the urine.
- The diagnosis of type 1 RTA is suggested by finding a hyperchloraemic acidosis in
association with an alkaline urine particularly if there is evidence of renal stone
Note: If [HCO3 > 15 mmol/l, then acid loading tests are required to establish the diagnosis.
- Treatment with NaHCO3 corrects the Na+ deficit, restores the extracellular fluid volume
and results in correction of the hypokalaemia. Typical alkali requirements are in the range
of 1 to 4 mmol/kg/day. K+ supplements are only rarely required. Sodium and potassium
citrate solutions can be useful particularly if hypokalaemia is present. Citrate will bind
Ca++ in the urine and this assists in preventing renal stones.
- Type 2 RTA is also called proximal RTA because the main problem is greatly impaired
reabsorption of bicarbonate in the proximal tubule.
- At normal plasma [HCO3], more than 15% of the filtered HCO3 load is excreted in the
urine. When acidosis is severe and HCO3 levels are low (eg <17 mmols/l), the urine may
become bicarbonate free.
- Symptoms are precipitated by an increase in plasma [HCO3]. The defective proximal
tubule cannot reabsorb the increased filtered load and the distal delivery of bicarbonate is
greatly increased. The H+ secretion in the distal tubule is now overwhelmed by
attempting to reabsorb bicarbonate and the net acid excretion decreases. This results in
urinary loss of HCO3 resulting in systemic acidosis with inappropriately high urine pH.
The bicarbonate is replaced in the circulation by Cl-.
- The increased distal Na+ delivery results in hyperaldosteronism with consequent renal
K+ wasting. The hypokalaemia may be severe in some cases but as hypokalaemia inhibits
adrenal aldosterone secretion, this often limits the severity of the hypokalaemia.
- Hypercalciuria does not occur and this type of RTA is not associated with renal stones.
- During the NH4Cl loading test, urine pH will drop below 5.5.
- Note that the acidosis in proximal RTA is usually not as severe as in distal RTA and the
plasma [HCO3] is typically greater than 15 mmol/l.
- There are many causes but most are associated with multiple proximal tubular defects
eg affecting reabsorption of glucose, phosphate and amino acids. Some cases are hereditary.
- Causes include vitamin D deficiency, cystinosis, lead nephropathy, amyloidosis and
medullary cystic disease.
- Treatment is directed towards the underlying disorder if possible.
- Alkali therapy (NaHCO3) and supplemental K+ is not always necessary. If alkali
therapy is required, the dose is usually large (up to 10 mmols/kg/day) because of the
increased urine bicarbonate wasting associated with normal plasma levels.
- K+ loss is much increased in treated patients and supplementation is required.
- Some patients respond to thiazide diuretics which cause slight volume contraction and
this results in increased proximal bicarbonate reabsorption so less bicarbonate is needed.
- This term is no longer used.
- Type 3 RTA is now considered a subtype of Type 1 where there is
a proximal bicarbonate leak in addition to a distal acidification defect.
- A number of different conditions have been associated with this type but most patients
have renal failure associated with disorders affecting the renal interstitium and tubules. In
contrast to uraemic acidosis, the GFR is greater than 20 mls/min.
- a useful differentiating point is that hyperkalaemia occurs in type 4 RTA (but
NOT in the other types).
- The underlying defect is impairment of cation-exchange in the distal tubule with
reduced secretion of both H+ and K+.
- This is a similar finding to what occurs with aldosterone deficiency and type 4 RTA can
occur with Addison's disease or following bilateral adrenalectomy.
- Acidosis is not common with aldosterone deficiency alone but requires some degree of
associated renal damage (nephron loss) esp affecting the distal tubule.
- The H+ pump in the tubules is not abnormal so patients with this disorder are able to
decrease urine pH to < 5.5 in response to the acidosis.
of RTA types
- The acidosis occurring in uraemic patients is due to failure of excretion of acid anions (particularly
phosphate and sulphate) because of the decreased number of nephrons. There is a major decrease
in the number of tubule cells which can produce ammonia and this contributes to uraemic acidosis.
- Serious acidosis does not occur until the GFR has decreased to about 20 mls/min. This
corresponds to a creatinine level of about 0.30-0.35 mmols/l.
- The plasma bicarbonate in renal failure with acidosis is typically between 12 & 20
mmols/l. Intracellular buffering and bone buffering are important in limiting the fall in
bicarbonate. This bone buffering will cause loss of bone mineral (osteomalacia).
- Most other forms of metabolic acidosis are of relatively short duration as the patient is either treated
with resolution of the disorder or the patient dies. Uraemic acidosis is a major exception as these patients
survive with significant acidosis for many years. This long duration is the reason why loss of bone mineral
is significant in uraemic acidosis but is not a feature of other causes of metabolic acidosis.
- Metabolic acidosis occurs with both acute and chronic renal failure and with
other types of renal damage. The anion gap may be normal or may be elevated.
- If the renal damage affects both glomeruli and tubules, the acidosis is a high-anion
gap acidosis. It is due to failure of adequate excretion of various acid anions due to
the greatly reduced number of functioning nephrons.
- If the renal damage predominantly affects the tubules with minimal glomerular damage,
a different type of acidosis may occur. This is called Renal Tubular Acidosis (RTA) and
this is a normal anion gap or hyperchloraemic type of acidosis. The GFR may be normal
or only minimally affected.
- Renal tubular acidosis is a form of hyperchloraemic metabolic acidosis which occurs
when the renal damage primarily affects tubular function without much effect on
glomerular function. The result is a decrease in H+ excretion which is greater than can be
explained by any change in GFR. If glomerular function (ie GFR) is significantly
depressed, the retention of fixed acids results in a high anion gap acidosis.
- Three main clinical categories or 'types' of renal tubular acidosis (RTA) are now
recognised but the number of possible causes is large. The mechanism causing the defect
in ability to acidify the urine and excrete acid is different in the three types.
- Incomplete forms of RTA also occur. The arterial pH is normal in these patients and
acidosis develops only when an acid load is present.
Type1 Type2 Type4
Yes Yes Yes
MinimumUrinepH >5.5 <5.5(butusually>5.5
PlasmapotassiumLow-normal Low-normal high
Renal stones Yes No No
- levels of environmental contamination with A. baumannii
correlate with patient colonization and infection. This organism
is very hardly and survives dessication.
- Acinetobacter are non-lactose fermenting, Gram-negative
coccobacilli that are strictly aerobic and non-motile.
- Acinetobacter baumanii is the most important species
associated with infections and nosocomial outbreaks
- Acinetobacter isolates are typically even more resistant than
Pseudomonas spp. to most antimicrobials, including broad-spectrum
cephalosporins, penicillins, fluoroquinolones and aminoglycosides.
- It causes a wide range of nosocomial infections including
ventilator-associated pneumonia, bacteraemia, urinary tract
infections, skin and wound infections and meningitis
- Acinetobacters form part of the normal bacterial flora of
the skin, particularly in moist regions such as the axillae,
groin and toe webs.
- Up to 25% of normal individuals carry cutaneous Acinetobacter,
and it is the most common gram-negative organism isolated from
the skin of hospital personnel.
- Dissemination of Acinetobacter in the environment can be a major
- It has been recovered from respiratory equipment, bed linen,
tables, patients' charts, sink traps, the floor and atmosphere,
especially in the vicinity of an infected or colonized patient
- Furthermore, Acinetobacter is able to persist in the environment
for several days, even in dry conditions, on particles and dust.
- Some strains are tolerant to soaps and disinfectants.
- The nosocomial spread of Acinetobacter is most often attributed
to exogenous contamination from equipment, environmental
surfaces and the hands of hospital personnel rather than endogenous
- Known resistance mechanisms include plasmid-mediated beta-lactamases,
which are also frequently associated with resistance to fluoroquinolones
- Chromosomal cephalosporinases may be responsible for the high
prevalence of ceftazidime resistance. However, the relationship
between observed antibiotic resistance patterns in vitro and the presence
of these beta-lactamases remains unclear. It is suggested that altered
penicillin-binding proteins and membrane impermeability may be the
major cause of high level resistance to beta-lactams, including imipenem
- Carbapenems are currently considered the antimicrobials of choice, although
epidemic outbreaks and endemic situations involving carbapenem-resistant
Acinetobacter species have been described
- Colistin, polymyxin B & ampicillin-sulbactam have all been
described in treatment of carbapenem-resistant strains
general - coronary artery disease accounts for over 30% of deaths in Western countries.
- ischaemic chest pain with is recent in origin, is more frequent, severe, or
prolonged than the patient's usual angina; is more difficult to control with drugs;
or is occurring at rest or with minimal exertion
- cardiac biomarkers are not elevated
- ischaemic symptoms with raised cardiac biomarkers
- STEMI: ST elevation
- NSTEMI: no ST elevation
(i) by life-style
- physical inactivity
(ii) by pharmacotherapy or lifestyle
- increasing age
- male gender
- family history
hyperacute (0-20 minutes)
- tall peaking T waves & progressive upward curving & elevation of ST segments
acute (minutes - hours)
- persistent ST elevation with gradual loss of R wave in the infarcted area.
ST segments begin to fall & there is progressive inversion of T waves
early (hours to days)
- loss of R wave and development of pathological Q waves in the area of ischaemia.
Return of ST segments to baseline with persistence of T wave inversion
indeterminate (days to weeks)
- pathological Q waves with persisting T wave inversion.
ST segments normalise (unless there is aneurysm)
old (weeks to months)
- persisting deep Q waves with normalised ST segments
Troponin I or T:
- troponin rise indicates myonecrosis & is a high risk feature in non ST elevation acute coronary syndrome
- troponin remains elevated for 5-14 days and therefore may not be useful for identifying early reinfarction
-troponin elevation is often delayed by 4-6 hours after infarction
- should be monitored for 48 hours serially & can be measured subsequently if there is suspected reinfarction
- more specific than CK for myocardial infarction & may be used to confirm a reinfarction
- reperfusion can be obtained with fibrinolytic therapy or PCI
- a combination of fibrinolysis and PCI can also be used
- CABG surgery may occasionally be more appropriate with particular anatomy
& may be considered as rescue therapy in patients who fail revascularisation
- PCI is the best available treatment; however, benefit depends on prompt access to service and
if delay is longer than 90 minutes until balloon inflation thrombolysis should be administered.
- PCI is clearly better in the presence of cardiogenic shock
- aspirin 300mg should be given to all patients with STEMI unless contraindicated
- both the VA Cooperative Study Group and the Canadian Multicentre Trial showed that aspirin reduces the
risk of death or myocardial infarction by 50% in patients with unstable angina or non-Q wave infarction
- clopidogrel should be given as a load 600mg to all patients who require a stent
& should be continued for at least 12 months; clopidogrel should be given to selected
patients given fibrinolysis. If urgent CABG is likely, clopidogrel should be withheld
- in the CURE trial, clopidogrel given in addition to aspirin within 24hrs of unstable angina symptoms led to significantly
reduced of cardiovascular death from 11.4% to 9.3% but was associated with a 1% absolute increase in major, non
life threatening bleeds as well as a 2.8% increase in major bleeds associated with CABG within 5 days
- ticlopidine & clopidogrel (thienopyridins) are second generation platelet inhibitors acting independently
& theoretically synergistically with aspirin
(i) with PCI: unfractionated heparin should be administered with dose dependent or whether IIb/IIIa
inhibitors are used; the role of enoxaparin in acute STEMI following PCI remains to be determined
(ii) with fibrinolysis: heparin or enoxaparin should be used fibrin-specific fibrinolytic
agents. The use of antithrombin therapy in conjuction with streptokinase is optional.
glycoprotein IIb/IIIa inhibitors:
- reasonable to use post primary PCI although data are conflicting regarding efficacy. They reduce mortality
the 30-day risk of non-fatal AMI by 38& in NSTEMI in patients undergoing PCI. They have not been shown to
be beneficial in the routine management of medically treated patients (GUSTO-IV-ACS)
- there are two classes of glycoprotein IIb/IIIa inhibitors
(i) murine monoclonal (eg abciximab)
(ii) 'small molecule' inhibitors (eg tirofiban & eptibatide)
- should be avoided with fibrinolytic therapy because of risk of bleeding; platelet infusion may treat significant
bleeding in patients receiving abciximab but not in those receiving tirofiban or eptifibatide)
risk stratification of
non ST elevation
(i) high risk consists of clinical features of ACS with any of the following:
- repetitive or prolonged (>10mins) ongoing CP
- elevated cardiac biomarkers
- persistent or dynamic ECG changes (ST depression or TWI)
- transient ST elevation
- cardiogenic shock
- sustained VT
- prior CABG
- percutaneous coronary intervention within 6 months
- presence of known diabetes with typical ACS features
- chronic renal failure with typical ACS features
(ii) intermediate risk consists of clinical features with any of the following:
- resolved chest pain that occurred at rest or was repetitive or prolonged
- age >65
- known CAD
- two or more of the following risk factors (hypertension, family history, active smoking or hyperlipidaemia)
- presence of known diabetes mellitus with atypical ACS features
- presence of chronic renal failure with atypical ACS features
- prior aspirin use
(iii) low risk
- presentation with clinical features of an acute coronary syndrome without intermediate or high risk features
non ST elevation
- high risk patients require aggressive medical management and coronary angiography
- intermediate risk patients require inpatient monitoring and investigation and provocative testing
- low risk patients can be discharged with follow-up
- earliest rise of CK & CK-MB occurs at 3-4 hours with a peak at 12-24 hours and normalisation by 48 hours
criteria for AMI in LBBB
(i) new LBBB
(ii) concordant ST elevation of >1mm
(iii) concordant ST depression of >1mm in V1, V2 or V3
(iv) discordant ST elevation of >5mm
- reduce myocardial oxygen demand through afterload reduction and may on improve myocardial
oxygen delivery through coronary vasodilation
- may lead to dramatic resolution of ischaemia in coronary vasospasm
- GISSI-3 and ISIS-4 trials failed to demonstrate mortality reduction from acute or chronic nitrates; nevertheless,
they remain first line therapies for symptomatic angina and when myocardial infarction is complicated by CCF
- iv beta blockers should be considered for patients with tachycardia or hypertension post infarct in the acute setting
- oral beta blockers decrease mortality after myocardial infarction and should be administered to all patients who can tolerate them
- SAVE trial showed that captopril in patients with EF<20% post AMI lead to a 21% reduction in mortality
- ISIS-4 showed a smaller reduction in mortality for all patients treated with captopril post AMI
- HOPE showed patients with vascular disease or high risk of atherosclerosis benefited from ramipril
- decrease risk of adverse ischaemic events in patients with CAD thrombolysis
(i) active bleeding or bleeding diasthesis (excluding menses)
(ii) significant closed head injury or facial trauma within 3 months
(iii) suspected aortic dissection
(iv) risk of intracranial haemorrhage (any prior ICH, ischaemic
stroke within 3 months, cerebral vascular lesion, brain tumour)
- risk of bleeding
(i) current use of anticoagulants (the higher the INR the higher the risk)
(ii) non-compressible vascular punctures
(iii) recent major surgery
(iv) prolonged CPR >10 minutes
(v) internal bleeding within 4 weeks
(vi) active peptic ulcer
- risk of ICH
(i) history of chronic, severe, poorly controlled hypertension
(ii) severe uncontrolled HTN on presentation (>180mmHg systolic; or >110mmHg diastolic)
(iii) ischaemic stroke more than 3 months previously
- ESSENCE trial showed that low molecular weight heparin (enoxaparin) reduced the combined
end point of death, MI or recurrent ischaemia at both 14 & 30 days when compared with heparin
- 8% of patients with MI will only display ST elevation in posterior or right precordial leads
- The widely used Atlanta classification categorizes acute
pancreatitis as mild or severe.
- pancreatitis is classified as severe any of the following 4 criteria are met:
(1) Organ failure with 1 or more of the following:
-shock systolic blood pressure <90 mm Hg),
- pulmonary insufficiency (PaO2 <60 mm Hg),
renal failure (serum creatinine level >176.8 ìmol/L after rehydration, and
gastrointestinal tract bleeding (>500mL in 24 hours);
(2) local complications such as:
- or abscess;
(3) at least 3 of Ranson’s criteria
(4) at least 8 of the APACHE II criteria.
- Pancreatic necrosis is the presence of a diffuse or focal area of nonviable
pancreatic parenchyma, often associated with peripancreatic necrosis.
- Severe acute pancreatitis with pancreatic or peripancreatic necrosis is also
referred to as necrotizing pancreatitis.
- Initially a sterile necrosis (mortality, 10%), necrotizing pancreatitis becomes
infected with bacteria of gut origin in 40% to 70% of cases2 and is then called
infected necrosis (mortality, 25%).
- Pancreatic pseudocyst is a collection of pancreatic juice enclosed by
a wall of fibrous or granulation tissue that develops as a result of a persistent
leak of pancreatic juice from the pancreatic duct.
- Pancreatic abscess is a circumscribed intra-abdominal collection of pus
that sometimes contains gas.
- It follows infection of a limited area of pancreatic or peripancreatic necrosis
and usually takes 4 to 6 weeks to evolve.
- From several large studies describing patients with severe
acute pancreatitis, the 2 most common causes of SAP are:
(i) chronic heavy alcohol use (approximately 40% of patients) and
(ii) gallstones (approximately 35% of patients).
- Less common causes of severe acute pancreatitis are:
(i) trauma to the pancreas,
(iv) complications from ERCP or surgery.
(v) cystic fibrosis
(vi) infectious causes including HIV, EBV, CMV & viral
hepatitis as well as mycoplasma & campylobacter
(vii) drugs, poisons & toxins including organophosphates
- azathiprine, thiazides, mercaptopurine, valproate,
didanosine, pentamidine, cotrimoxazole & scorpion
- In about 20% of patients, no cause can be identified.
- Severe acute pancreatitis occurs in men more often than in women.
- Alcoholic pancreatitis is more common among men;
gallstone pancreatitis is more common among women.
- Patients with SAP typically complain of fairly sudden onset of severe upper
abdominal pain, radiating to the back, often associated with nausea and vomiting.
- Marked elevations in serum amylase and/or lipase (>3 times the upper limit
of normal) support the diagnosis of pancreatitis in a patient with severe abdominal
pain. However, modest elevations of pancreatic enzymes may be observed in other
- In the presence of pancreatitis, an increase in liver enzyme values, especially
of alanine aminotransferase to more than 3 times normal, suggests a biliary cause.
Abdominal ultrasonography can be used to detect gallstones,
although bowel gas may limit its accuracy in the acute setting.
Contrast enhanced computed tomography (CT) is useful for differentiating SAP from
other conditions presenting with abdominal pain and elevated pancreatic enzymes.
It also helps to delineate local complications associated with SAP:
- Pancreatic or peripancreatic necrosis is diagnosed when some or all
of the pancreas or surrounding area fails to enhance with contrast.
- To determine whether a necrotic area is infected, it can be sampled by fine-needle
aspiration under CT guidance and analyzed with Gram stain and culture for evidence
of gut-derived bacteria and/or fungal organisms.
Magnetic resonance imaging is better than CT for distinguishing between
an uncomplicated pseudocyst and one that contains necrotic debris
MRCP and ERCP
Magnetic resonance cholangiopancreatography and endoscopic ultrasonography
can detect small bile duct stones as a cause of SAP.
- The initial treatment of SAP is supportive. Aggressive fluid resuscitation,
oxygen supplementation, and pain relief are critical.
- Interventions used in the past aimed at resting the pancreas (nasogastric suction and
acid suppression), diminishing secretion of enzymes (glucagon and somatostatin
administration), and countering the damaging effects of enzymes (use of
aprotinin, gabexate, or lexipafant) do not improve outcomes
- In the past, patients with severe acute pancreatitis were administered parenteral nutrition
in an effort to avoid stimulation of the pancreas. More recently, it has been shown in animal
models that enteral nutrition prevents intestinal atrophy and improves the barrier function of
the gut mucosa.
- Three RCTs have demonstrated that enteral feeding is not only safe and feasible but
is also associated with fewer infectious complications, and is less expensive than TPN.
- Enteral feeding should be commenced whereever possible
Prevention of Pancreatic Infection:
- Pancreatic or peripancreatic infection develops in 40% to 70% of patients
with pancreatic necrosis and is the leading cause of morbidity and mortality
- Infection usually occurs at least 10 days after the onset of SAP.
- Methods to reduce the incidence of infection in patients with SAP include:
(i) selective gut decontamination - unproven
(ii) prophylactic systemic antibiotics - use of broad spectrum antibiotics is
supported by metanalysis data but may lead to fungal superinfection
- If fever or leukocytosis persists or develops beyond 7 to 10 days without an obvious
source of infection, fine-needle aspiration of the necrotic area should be performed
to rule out infection.
- A metaanalysis of 4 RCTs of endoscopic sphincterotomy
in patients with severe biliary pancreatitis showed that sphincterotomy
reduced complications and mortality of SAP in patients with biliary obstruction
- The role of early ERCP in patients without biliary obstruction or cholangitis is unclear.
One study reported higher mortality after ERCP in such patients.
- An accepted practice is to perform endoscopic sphincterotomy in patients with
evidence of biliary obstruction (cholangitis, jaundice) or elevated liver test results
except in those with rapidly normalizing test results.
- Debridement by surgery or a less invasive technique is indicated in
patients with infected necrosis. Outcomes are better if surgery is delayed
until the necrosis has organized, usually about 4 weeks after disease onset.
- The preferred surgical procedure for SAP is necrosectomy (debridement) with
the placement of wide-bore drains for continuous postoperative irrigation.
- For patients who are poor surgical candidates or who have well-contained infection,
minimal-access necrosectomy by either percutaneous or endoscopic routes
has shown encouraging results.
- For patients with biliary pancreatitis, cholecystectomy should be performed during
the initial hospitalization or after the resolution of intraabdominal inflammation to
prevent recurrence. In patients too ill to undergo cholecystectomy, endoscopic
sphincterotomy is an alternative.
- mild acute pancreatitis has a mortality rate of less than 1%
- the death rate for severe acute pancreatitis is 10% with sterile
and 25% with infected pancreatic necrosis.
- Approximately half the deaths of patients with SAP occur within 2 weeks of
onset. Early morbidity and mortality in patients with SAP are attributable to
organ failure secondary to systemic inflammatory response syndrome.
- The remaining deaths occur because of later complications of infected necrosis.
indications for CT
indications for surgery
- Numerous papers highlight the lack of a universal definition for ARF in ICU. One
review of the subject found 26 different definitions of postoperative ARF in 26 studies
- Even a consensus conference of intensivists and nephrologists on the subject in 2000
could not provide an adequate, universal definition. This makes it difficult to draw
conclusions from all the individual trials that are published.
- Acute renal failure (ARF) is a common problem in intensive care. It is said to have an
incidence of 10-25%. The diagnosis of ARF is not difficult, although the term ARF
encompasses a broad range of definitions with no universally accepted definition
- A specific definition of disease with tight exclusion criteria is essential in the design of
clinical studies of a heterogeneous syndrome
Particular issues around definition include
- Is the absolute increase or the rate of increase of serum creatinine and urea important for
the definition? Are acid-base imbalance, serum potassium level and urine output
significant in the diagnosis?
(ii) Chronic renal impairment:
- How is this incorporated into the definition and what impact does it have on diagnosis,
management and outcome?
- Should reversible elements be corrected before the definition is applied? For example, is
the correction of mean arterial pressure and filling pressures to normal physiological
values necessary before ARF can be diagnosed?
(iv) Nephrotoxic drugs:
- what are the implications of nephrotoxic drugs, e.g. gentamicin or non-steroidal anti-
inflammatory drugs, for the definition and the aetiology?
- The underlying pathophysiological process is thought to be important to outcome.
Should this be included if it is known or should it be categorized according to aetiology?
(vi) Post-renal ARF:
- Causes of postrenal ARF often have a very different natural history and outcome; if this
is identified, should they be excluded?
(vii) Confounding factors:
- does an upper gastrointestinal haemorrhage or rhabdomyolysis need to be ruled out?
- The combined published results for ARF, its incidence and outcome are:
o An incidence of 10-25%.
o Patients who are admitted with or develop ARF on the ITU have an overall mortality of 23-80%
o Patients with ARF not requiring RRT have a mortality of 10-53%
o Patients who develop ARF that requires RRT have a higher mortality of 57-80%
o Of those patients with ARF who receive RRT and survive, only 5-30% require longer-term dialysis.
o The mortality of patients who are admitted to ITU with ARF, or who go on to develop ARF, remains high.
- This wide variation in published results (up to six-fold) is due in part to the following
problems that are not specifically addressed in the majority of studies:
(i) Inclusion criteria vary between studies because the definition of what constitutes ARF is so variable.
(ii) There is significant heterogeneity of the population in terms of severity of illness and demographics.
(iii) Many different disease processes can cause ARF, so one may not be comparing like with like.
Is it the incidence of ARF that varies or the incidence of the disease process in different centres?
(iv) Different disease processes have different incidences of renal damage and mortality.
(v) Some centres are moving to the early initiation of RRT, often prior to the
development of 'criteria' to define ARF. Should this group be considered separately?
(vi) Outcome analysis varies: 14-day, 15-day, 28-day and 30-day mortality have all been used
as endpoints. Alternatively, ICU, in-hospital or 1-year mortality figures have been used.
- this is used to define a syndrome where the principle source of damage is within
the kidney and where typical structural changes can be seen on microscopy
- pathogenesis of parenchymal renal failure is generally immunological and varies
from vasculitis to interstitial nephropathy
- more than 1/3rd of patients who develop ARF in ICUs have chronic renal dysfunction
due to factors such as age related changes, long-standing changes, long-standing
hypertension, diabetes or renal vascular disease
drug-induced renal failure
- many cases of drug-induced renal failure improve rapidly on removal of the offending
agent and accordingly a drug history is important in all cases of renal failure
- a form of ARF that occurs in the setting of severe liver dysfunction in the absence of other
known causes of ARF. Typically, it presents as progressive oliguria with a very low urinary
- pathogenesis is not well understood but it is thought to involve severe vasoconstriction
(ii) differential diagnosis:
- other causes of acute renal failure are more common than hepatorenal syndrome in severe
liver disease. They include sepsis, paracentesis-induced hypovolaemia, alcoholic cardiomyopathy
or any combination of these
(iii) prevention and treatment:
- the use of albumin in patients with SBP has been shown to reduce renal failure in an RCT
- studies suggest vasopressin derivatives (terlipressin) may improve GFR
- accounts for 5-10% of cases of ARF in ICU depending on the setting
- pathogenesis involves pre-renal, renal and post renal factors
- typically seen following major trauma, drug overdose & vascular embolism
- treatment principles are based on retrospective data and include aggressive fluid resuscitation,
elimination of causative agents, correction of compartment syndromes, alkalinisation of urine
(pH>6.5), and maintenance of polyuria
- Renal replacement therapy (RRT) is now a routine element of organ support in the
intensive therapy unit (ITU). Yet despite great improvements in the recognition
and management of ARF, including RRT, the mortality of patients who are admitted to
ITU with ARF, or who subsequently develop ARF, remains high at 23-80%.
- if the cause of ARF has been removed and he patient has become physiologically stable slow recovery
occurs over 4-5 days to 3-4 weeks; in some cases the urine output can be above normal for several days
- the fundamental principle of acute renal failure is to treat its cause.
- if pre-renal factors contribute these must be identified and haemodynamic
resuscitation quickly instituted
- intravascular volume must be maintained or rapidly restored & oxygenation must
be maintained; an adequate haemoglobin concentration should be maintained
- once intravascular volume has been restored, some patients remain hypotensive.
In these patients autoregulation of renal blood flow may be lost & increasing MAP
with vasopressors may increase GFR; the role of additonal fluid in a patient with
normal blood pressure and cardiac output is questionable
- despite the above measures pre-renal renal failure may develop if cardiac output
(i) 'low dose' dopamine
- evidence of efficacy or safety is lacking; however, this agent is a tubular diuretic
and occasionally increases urine output
- randomised controlled trial evidence in critically ill patients shows that low-dose
dopamine is no more effective than placebo in prevention of renal dysfunction; however,
in patients with low cardiac output dopamine may increase cardiac output, renal blood
flow and GFR (as would dobutamine or milrinone)
- animal experiments offer some encouraging findings; however, no human data exist to
support its clinical use
(iii) loop diuretics
- these agents may protect the loop of Henle from ischaemic from decreasing its transport
related workload; however, there are no double blind randomised controlled trials proving
that these agents reduce the incidence of renal failure
- several studies support the view that loop diuretics may decrease the need for dialysis
in patients developing acute renal failure. They appear to achieve this by inducing polyuria
which results in the prevention or easier contorl of volume overload, acidosis & hyperkalaemia
- because avoiding dialysis simplifies treatment and reduces the cost of care, loop diuretics
may be useful
(iv) other agents
- other experimental agents include theophylline, urodilatin and anaritide (a synthetic atrial
general investigations include:
(i) examination of urinary sediment and exclusion of a urinary tract infection (most if not all patients)
(ii) careful exclusion of nephrotoxins (all patients)
(iii) exclusion of obstruction (some patients)
special investigations may include:
(i) CK and myoglobin (for rhabdomyolysis)
(ii) chest x-ray, blood film
(iii) specific antibodies (anti-GBM, antidsDNA, anti-smooth muscle etc)
(iv) LDH, haptoglobin, unconjugated bilirubin
(vi) Bence Jones Proteins
(vii) renal biopsy
- differentiation of prerenal and renal failure has limited clinical implication
because they are part of the same continuum and treatment is the same
- obstruction to urine outflow is the most common cause of functional
renal impairment in the community but is uncommon in the ICU
- involves humoral and mechanical factors
- typical causes include bladder neck obstruction from an enlarged prostate, ureteric obstruction
from pelvic tumours or retroperitoneal fibrosis, papillary necrosis or large calculi
- clinical presentation may be acute or acute on chronic in patients with long standing calculi.
It may not always be associated with oliguria.
diagnostic criteria for hepatorenal syndrome
- this form of ARF is the most common in ICUs
- indicates that the kidney malfunctions predominantly because of the systemic factors which
diminish renal blood flow and decrease GFR or by alteration of intraglomerular haemodynamics
- renal blood flow is decreased by:
(i) decreased cardiac output
(iii) raised intraabdominal pressure (decompression should be considered when
the intrabdominal pressure is greater than 25-30mmHg above the pubis)
- in septic patients with hyperdynamic circulations there may be adequate global blood flow to the kidney but intrarenal shunting
away from the medullar causing medullary ischaemia or efferent arteriolar dilation thus decreasing GFR
- if the systemic cause of renal failure is rapidly removed renal function improves relatively rapidly
- several mechanisms are involved in the development of renal injury in pre-renal failure:
(i) ischaemia of the outer medulla with activation of tubuloglomerular feedback
(ii) tubular obstruction from casts of exfoliated cells
(iii) interstitial oedema secondary to back diffusion of fluid
(iv) humorally mediated afferent arteriolar renal vasoconstriction
(v) inflammatory response to cell injury and local release of mediators
(vi) disruption of normal cellular adhesion to the basement membrane
(vii) radical oxygen species induced apoptosis
(viii) mitogen-activated protein kinases-induced renal injury
- Right heart failure is characterized by a low cardiac output, hypotension, hepatic enlargement and raised JVP.
- Cardiogenic shock due to right ventricle failure has a mortality rate comparable to left ventricle failure
Right ventricular function:
- In systole, because of the constraints imposed by the pericardium, the high pressure in the left ventricle
and the heart's anatomical configuration, the septum intrudes into the right ventricular cavity.
- The right ventricle is better suited to volume overload than the left, but increased afterload is more detrimental.
- The low pressures in the right side of the heart arise as a result of the thin walled ventricle and highly compliant pulmonary circulation.
- The lack of myocardial bulk means that contractility cannot be maintained in the face of increased pulmonary resistance.
- In pulmonary hypertension, dilatation occurs as a compensating mechanism.
Right heart failure:
- In all cases, there is a critical point at which ventricular dilatation cannot compensate.
- Consequently, there is reversal of the ventricular septal pressure gradient, abnormal septal movement, rising atrial pressures and TR.
- The abnormal volume and pressure loading stress the right side of the heart, resulting in increased oxygen demand, decreased
coronary driving pressures and worsening right ventricle output. The global reduction in left sided preload contributes to systemic
hypotension exacerbated by septal dyskinesia and reversal of the interventricular dependence pressures. This in turn further lowers
coronary perfusion pressures. This vicious cycle has been termed auto-aggravation.
problems with clinical diagnosis:
(i) right ventricular failure may exist in the absence of peripheral oedema.
(ii) peripheral oedema is not discriminatory for right heart failure.
(iii) elevated jugular venous pressures and abnormal waveforms may be distorted by
mechanical ventilation, body habitus and lung hyperinflation in COPD patients.
(iv) signs such as hypotension, tachycardia, tachypnoea & hepatomegally are nonspecific.
- Changes in the pulmonary vasculature and the cardiac shadow may allow the diagnosis of underlying
pathology potentially associated with pulmonary hypertension and, by inference, right ventricular involvement
- Echocardiography can show structural change, dynamic responses to intervention and
allows quantitative and qualitative measurements to refine the significance of findings.
- With transthoracic echocardiography (TTE) multiple measurements, ratios and estimates
have been used to assess quantitative and qualitative parameters including:
(i) tricuspid regurgitation;
(ii) long axis cavity size,
(iii) short axis septal kinetics,
(iv) apex loses triangle shape;
(v) right ventricular end-diastolic area/left ventricular end-diastolic area (>0.6 or >1);
(vi) left inferior hypokinesis;
(vii) right ventricle size in comparison to left ventricle;
(viii) right ventricular end diastolic volume diameter >30mm at level of mitral valve from left precordial view;
(ix) loss of inspiratory collapse of inferior vena cava
(x) dilation of pulmonary artery,
(xi) tricuspid regurgitation;
Right heart catherisation
- Right heart catheterisation and thermodilution are invasive but can provide nearly continuous values, in
contrast to other modalities, for right heart cardiac output and continuous right heart pressures.
- Natriuretic peptides induced by myocardial stress and dilatation are an attractive means to detect heart failure and to monitor
response to treatment. They have been used to stratify outcome in acute pulmonary embolismand in long-term follow-up for
patients with surgically corrected tetralogy of Fallot, and also as predictors of mortality in hypertension, renal failure, amyloidosis,
sepsis and diabetes.
- Plasma levels of natriuretic peptides have been shown to be proportional to the magnitude
of right ventricle dysfunction and correlate negatively with the ejection fraction.
- Levels vary in populations, sex, age groups and between various disease states. In the critically ill patient population natriuretic
peptides may be elevated due to underlying or coexisting heart disease or lung disease.
- No selective right heart inotrope exists.
- Augmentation of contractility can be achieved by b-mimetics, calcium sensitizers and phosphodiesterase
inhibitors. The problem is that without afterload manipulation, increasing right heart contractility and hence output,
increases myocardial oxygen consumption but without a systemic benefit.
- The aim in the management of right ventricular dysfunction is to disrupt the cycle of auto-aggravation.
- For a given contractile state, reducing afterload will increase the ejection fraction.
- Similarly in a normal afterload state, augmentation of contractility raises the right ventricular ejection fraction.
- Volaemic status is difficult to judge. In a dilated decompensated ventricle with elevated atrial pressures, volume reduction is most likely to
improve the right ventricular ejection fraction. In the absence of elevated right atrial pressure then monitored volume challenges are justified.
- Reduction in myocardial oxygen demand or improvements in coronary perfusion must also be considered.
- Failure can be defined as the point at which the right ventricle fails to compensate for an increased ventricular volume, as each fibre
has an optimal stretch to allow maximal pressure generation, which, when exceeded, results in dilatation and eventually ventricular failure.
- Determination of preload is problematical but the presence of high right atrial filling pressures is indicative of elevated right ventricular pressures,
which extrapolates to a raised ventricular volume. This may not necessarily be true in all cases and depends on the compliance of the ventricle.
- In chronic elevation of right atrial pressures the pressure may be high, but this is a poor predictor of volume response, the patient may
therefore still be volume recruitable and sequential monitored fluid challenges are justified.
- The appearance of a dilated right ventricle with a reduced ejection fraction, however, should prompt a reduction in preload in a patient who is
not volume responsive (as defined by lack of alteration in heart rate, blood pressure, cardiac and urine output).
- The effect of therapy can be monitored by sequential echocardiography or by using right heart catheterization and, ideally, continuous measurement.
The converse is true though: sequential volume challenges monitored by pulmonary artery pressure changes in the absence of reversed right ventricle
interdependence will increase cardiac output, up to the individualized optimal filling point.
- The calcium sensitizing, lusitropic agent, levosimendan has been shown to provide a survival advantage in
heart failure trials. In a pilot study of levosimendan in early ARDS, Morelli et al. demonstrated that a reduction
in the pulmonary vascular resistance by levosimendan improved right ventricular function.
- Inotropes may provide a benefit in instances where ischaemia related to hypotension is a problem.
- They elevate the mean arterial pressure, coronary artery perfusion and may, consequently, reduce myocardial work.
- Vasotropic agents such as noradrenaline, phenylephrine and vasopressin may elevate diastolic pressures and
thus improve myocardial oxygenation. The benefit is lost once the right ventricle consumes more oxygen, to maintain
output, in the face of the elevated afterload.
- Phosphodiesterase inhibitors such as milrinone and amrinone inhibit the phosphodiesterase
enzymes responsible for cAMP/cGMP breakdown, augmenting myocardial contractility.
- The advantage of this drug class is that the mechanism is independent of b-adrenoceptor states and does not
increase myocardial oxygen demand. Nebulized milrinone, interestingly, has been shown to have an additive
effect with prostaglandin I2 in terms of pulmonary vasodilation.
- Hypoxaemia and hypercarbia worsen pulmonary artery pressures as does positive end expiratory pressure (PEEP), intrinsic PEEP
and high tidal volumes. Optimization of these variables needs to occur before pharmacological manipulation is undertaken.
- The poor contractile reserve of the right ventricle means that the primary modality for treatment of acute right ventricle
dysfunction secondary to elevated pulmonary artery pressures is by means of selective pulmonary vasodilation.
- Acutely, afterload reduction may be effected by using localized (inhaled) or systemic vasodilators. The consequences
of selected pulmonary vasodilation are of decreased resistance (and consequently afterload), improved VQ matching
and decreased arterial hypoxaemia.
- Prostaglandins can be given by inhalation, systemically or subcutaneously.
- The vasodilatory effects are mediated by nitric oxide release and interaction at a local level with the vascular endothelial smooth
muscle. Prostaglandin E1 systemically undergoes significant first pass pulmonary metabolism but with lower systemic pressures
and resistance, adversely altering the ventilation-perfusion matching and subsequently arterial oxygenation.
- When infused or as an aerosolized agent it is less effective than nitric oxide or aerosolized prostaglandin I2. Iloprost is
a stable carbacycline analogue of prostaglandin I2, a short acting natural prostaglandin. The vascular spillover of inhaled
iloprost, in combination with its prolonged plasma half-life, results in its systemic actions of lowered mean arterial pressure
and systemic vascular resistance.
- Nebulized prostaglandins are attractive in that they have limited systemic effects, are cheap and do not require specialized
delivery systems. The particle size, however, cannot easily be controlled and hence inefficiency of delivery may be significant
resulting in higher doses with potential systemic spillover.
- Inhaled nitric oxide (iNO), by virtue of its localized vascular endothelial action, through cGMP generation and its interaction
with calcium gated potassium channels and protein kinase G as well as cGMP independent paths, acts as pulmonary vasodilator.
Its effects are limited to the ventilated areas of the lung, with minimal
systemic overspill because of its rapid inactivation by haemoglobin
- No outcome benefit has yet been demonstrated in responders,
however, although oxygenation and pulmonary resistance do improve.
- Withdrawal of nitric oxide has been shown to result in rebound pulmonary hypertension
- Inhaled nitric oxide requires specialized delivery systems and the side-effect profile is significant, with platelet dysfunction,
myocardial depression, renal failure and the formation of toxic compounds such as peroxynitrites. The side effects are dose
dependent and although recommended doses are under 10 ppm quantities up to 80 ppm have been used.
- Sildenafil is a phosphodiesterase V enzyme, whose inhibition prolongs the
action of cGMP, with the overall effect of reducing pulmonary vascular tone.
- Tadalafil and vardenafil, members of the same class of phosphodiesterase inhibitors, have similar effects but of different
magnitude and duration. Sildenafil has been evaluated in decompensated right ventricular dysfunction, but its lack of an
intravenous preparation limits its use.
- Systemic vasodilators such as sodium nitroprusside, glyceryl trinitrate and hydralazine all reduce pulmonary afterload but at the expense
of systemic hypotension,decreasing coronary ostial perfusion pressures and potentially leading to a deleterious preload reduction,
exacerbating the dysfunction of the right ventricle, already compromised because of high right ventricular end diastolic pressure, through
ischaemia. Hence selective pulmonary vasodilators are more desirable in reducing afterload than global agents.
- Neseritide is a recombinant version of BNP. Its actions, when infused, are identical to the in-vivo effects of BNP (natriuresis,
sympathetic dampening and suppression of the renin- angiotensin axis by increasing cGMP). It reduces both preload and afterload,
consequently improving cardiac output without inotropy. Concerns exist over the decreased 30-day survival and its adverse impact
on renal function.
- In addition the systemic side effect can be that of hypotension and subsequently, decreased coronary perfusion pressures.
- To date it has not been evaluated in pure right heart failure.
- The distending alveolar pressure, when transmitted through the pulmonary capillary bed, determines the opening pressure
of the pulmonary artery valve.
- The greater the tidal volume the greater the impedance and hence the myocardial power generation has to be increased.
- Pleural pressure is transmitted to the myocardium because of the constricting pericardium, which limits the extent of
ventricular distension. Thus for an increase in pleural pressures a consequently higher preload is required to maintain the
right ventricular end diastolic volume
- A right ventricular friendly strategy is to set PEEP to limit gas trapping with prolonged expiratory times and to utilize as low a tidal
volume and respiratory rate as possible without deleterious ventilatory consequences
- The management of acute right ventricular infarction should follow standard guidelines for the reperfusion of occluded coronary arteries.
- Pacing, where indicated, has been shown to reduce mortality in biventricular failure and
should be considered in order to restore atrioventricular synchrony to ensure adequate preload
- Right ventricular assist devices may be appropriate in particular circumstances
- The cations normally present in urine are Na+, K+, NH4+, Ca++ and Mg++.
- The anions normally present are Cl-, HCO3-, sulphate, phosphate and some organic anions.
- Only Na+, K+ and Cl- are commonly measured in urine so the other charged
species are the unmeasured anions (UA) and cations (UC).
Urinary Anion Gap = [Na+]+ [K+] - [Cl-]
- The urinary anion gap can help to differentiate between GIT and renal causes of a
hyperchloraemic metabolic acidosis.
- It has been found experimentally that the Urinary Anion Gap (UAG) provides a rough
index of urinary ammonium excretion. Ammonium is positively charged so a rise in its
urinary concentration (ie increased unmeasured cations) will cause a fall in UAG
- Hyperchloraemic acidosis can be caused by:
(i) Loss of base via the kidney (eg renal tubular acidosis)
(ii) Loss of base via the bowel (eg diarrhoea).
(iii) Gain of mineral acid (eg HCl infusion).
- If the acidosis is due to loss of base via the bowel then the kidneys can respond
appropriately by increasing ammonium excretion to cause a net loss of H+ from the body.
The UAG would tend to be decreased, That is: increased NH4+ (with presumably
increased Cl-) => increased UC =>decreased UAG.
- If the acidosis is due to loss of base via the kidney, then as the problem is with the kidney
it is not able to increase ammonium excretion and the UAG will not be increased.
- Experimentally, it has been found that patients with diarrhoea severe enough to cause
hyperchloraemic acidosis have a negative UAG (average value -27 +/- 10 mmol/l) and
patients with acidosis due to altered urinary acidification had a positive UAG.
- An osmole is the amount of a substance that yields, in ideal solution, that number of
particles (Avogadro's number) that would depress the freezing point of the solvent by 1.86K
- Osmolality is measured in the laboratory by machines called osmometers. The units of
osmolality are mOsm/kg of solute
- Osmolarity is calculated from a formula which represents the solutes which under ordinary
circumstances contribute nearly all of the osmolality of the sample. There are many such
formulae which have been used. One is:
Calculated osmolarity = (2 x [Na+]) + [glucose] + [urea]
- The osmolar gap is the difference between the 2 values: the (measured) osmolality and
the (calculated) osmolarity (which is calculated):-
Osmolar gap = Osmolality - Osmolarity
- An osmolar gap > 10 mOsm/l is often stated to be abnormal.
Importance of the type of osmometer
- Only osmometers using freezing point depression method should be used for determining
this calculation because they are the only type of osmometer that can detect all the volatile
alcohols which can abnormally increase the osmolar gap. Vapour pressure osmometers can't do this
Significance of an elevated osmolar gap
- An elevated osmolar gap provides indirect evidence for the presence of an abnormal
solute which is present in significant amounts. To have much effect on the osmolar gap,
the substance needs to have a low molecular weight and be uncharged so it can be present
in a form and in a concentration (measured in mmol/l) sufficient to elevate the osmolar
- Ethanol, methanol & ethylene glycol are three such solutes that, when present in
appreciable amounts, will cause an elevated osmolar gap. If you suspect that your patient
may have ingested one of these substances than you should determine the osmolar gap.
- if the ethanol levels are measured they can be added to the calculated osmolarity to
exclude the presence of an additional contributer to the osmolar gap. [NB: To convert
ethanol levels in mg/dl to mmol/l divide by 4.6. For example, an ethanol level of 0.05% is
50mg/dl. Divide by 4.6 gives 10.9mmols/l]
- The Delta Ratio is sometimes useful in the assessment of metabolic acidosis.
- The Delta Ratio is defined as:
Delta ratio = (Increase in Anion Gap / Decrease in bicarbonate)
- In order to understand this, consider the following:
- If one molecule of metabolic acid (HA) is added to the ECF and dissociates, the one H+
released will react with one molecule of HCO3- to produce CO2 and H2O. This is the
process of buffering. The net effect will be an increase in unmeasured anions by the one
acid anion A- (ie anion gap increases by one) and a decrease in the bicarbonate by one.
- if all the acid dissociated in the ECF and all the buffering was by bicarbonate, then the
increase in the AG should be equal to the decrease in bicarbonate so the ratio between
these two changes (which we call the delta ratio) should be equal to one. The delta ratio
quantifies the relationship between the changes in these two quantities.
- the above assumptions about all buffering occurring in the ECF and being totally by
bicarbonate are not correct. Fifty to sixty percent of the buffering for a metabolic acidosis
occurs intracellularly. This amount of H+ from the metabolic acid (HA) does not react
with extracellular HCO3- so the extracellular [HCO3-] will not fall as far as originally
predicted. The acid anion (ie A-) however is charged and tends to stay extracellularly so
the increase in the anion gap in the plasma will tend to be as much as predicted.
- Overall, this significant intracellular buffering with extracellular retention of the
unmeasured acid anion will cause the value of the delta ratio to be greater than one in a
high AG metabolic acidosis.
Sources of error:
- Inaccuracies can occur for several reasons, for example:
(i) Calculation requires measurement of 4 electrolytes, each with a measurement error
(ii) Changes are assessed against 'standard' normal
values for both anion gap and bicarbonate concentration.
- Hyperchloraemic normal anion gap acidosis
- A low ratio occurs with hyperchloraemic normal anion gap acidosis. The reason here is
that the acid involved is effectively hydrochloric acid (HCl) and the rise in plasma
[chloride] is accounted for in the calculation of anion gap (ie chloride is a 'measured
- The result is that the 'rise in anion gap' (the numerator in the delta ration calculation)
does not occur but the 'decrease in bicarbonate' (the denominator) does rise in numerical
- The net of of both these changes then is to cause a marked drop in delta ratio,
commonly to < 0.4
0.4 - 0.8
- Consider combined high AG & normal AG acidosis BUT note
that the ratio is often <1 in acidosis associated with renal failure
1 to 2
- Usual for uncomplicated high-AG acidosis.
- Lactic acidosis: average value 1.6
- DKA more likely to have a ratio closer to 1 due to urine ketone loss
(esp if patient not dehydrated)
- A high delta ratio can occur in the situation where the patient had quite an elevated
bicarbonate value at the onset of the metabolic acidosis. Such an elevated level could be
due to a pre-existing metabolic alkalosis, or to compensation for a pre-existing
respiratory acidosis (ie compensated chronic respiratory acidosis).
- The term anion gap (AG) represents the concentration of all the unmeasured anions in
the plasma. The negatively charged proteins account for about 10% of plasma anions and
make up the majority of the unmeasured anion represented by the anion gap under normal
- the AG = [Na+] + [K+] - [Cl-] - [HCO3-] and a the upper range of normal is about 15
Major Clinical Uses of the Anion Gap
(i) To signal the presence of a metabolic acidosis and confirm other findings
- If the AG is greater than 30 mmol/l, than it invariably means that a metabolic acidosis is
present. If the AG is in the range 20 to 29 mmol/l, than about one third of these patients
will not have a metabolic acidosis.
(ii) Help differentiate between causes of a metabolic acidosis:
-high anion gap versus normal anion gap metabolic acidosis.
The effect of albumin & phosphate
- Albumin is the major unmeasured anion and contributes almost the whole of the value
of the anion gap.
- Every one gram decrease in albumin will decrease anion gap by 2.5 to 3 mmoles. A
normally high anion gap acidosis in a patient with hypoalbuminaemia may appear as a
normal anion gap acidosis.
- This is particularly relevant in Intensive Care patients where lower albumin levels are
- the 'normal anion gap depends on the serum phosphate and the serum albumin.
anion gap = 0.2 x [albumin] (g/L) + 1.5 x [phosphate] (mmol/L)
metabolic acidosis with increased anion gap:
Phenformin, paraldehyde, propylene glycol, pyroglutamic acidosis
Ethanol ketoacidosis, ethylene glycol
Salicylates, starvation ketoacidosis, solvent
metabolic acidosis with normal anion gap:
Ureteroenterostomy (K+ decreased)
Small bowel fistula (K+ decreased)
Extra chloride (K+ increased)
Diarrhoea (K+ decreased)
Carbonic anhydrase (K+ decreased)
Renal tubular acidosis (K+ decreased - type 1)
Addison's disease (K+ increased)
Pancreatic fistula (K+ decreased)
- Most critically ill patients are unable to effectively clear secretions that accumulate in
the central and peripheral airways. This can be due to factors such as:
(i) increased secretion production,
(ii) impaired cough reflex,
(iii) weakness, and
- Adjunctive respiratory therapy addresses many of these concerns to prevent and
treat respiratory complications that are encountered in the critically ill patient.
- percussion of the chest can aid in secretion clearance.
- It is performed by clapping cupped hands over regions of the thorax that are affected
in a rhythmic fashion or using mechanical devices that mimic the same action.
2. High-frequency chest compression (HFCC):
- relies on rapid pressure changes to the respiratory system during expiration to enhance
movement of mucus in the peripheral airways to the central airways for clearance. This
method employs a vest worn by the patient that is attached to an air-pulse generator. It is
difficult to apply this technique to most critically ill patients because the size of the vest
covering the thorax may prevent adequate monitoring.
3. Manual hyperinflation
- Typically, the lungs are inflated slowly to one and one-half to two times the tidal
volume or peak airway pressures of 40 cm H2O as measured by a manometer.
- It is held at end inspiration with an inspiratory pause to allow for filling of alveoli with
slow time constants.
- The goal of manual hyperinflation is to recruit atelectatic lung regions to improve
oxygenation and improve clearance of secretions.
- Contraindications include hemodynamic compromise and high intracranial pressure.
- There is also a risk of barotrauma because of preferential inflation of open lung regions
that are highly compliant compared with collapsed regions.
4. Positioning & mobilization:
- Mobilization of patients in the ICU either through active or passive limb exercises may
improve overall patient well-being and in the long term may lead to better patient outcomes.
- Positioning also plays an important role. Position of the patient with the head of the bed
elevated at least 30 degrees significantly reduces the risk of aspiration and ventilator-
- Positioning of selected individuals with unilateral lung disease on their side with the
affected side up can lead to improved ventilation-perfusion matching (by gravitational
increased perfusion to the dependent "good" side).
- If atelectasis secondary to retained secretions is the cause, having the affected side up
leads to postural drainage.
5. tracheal suction
- Used in conjunction with other techniques to mobilize secretions from the peripheral
airways to the central airways, suctioning is an effective way of removing secretions to
improve bronchial hygiene.
- Because of the anatomic arrangement of the large central airways, the suction catheter
most often enters the right mainstem bronchus compared with the left mainstem
- Complications with suctioning include hypoxemia, especially in the setting of a
ventilator disconnect, increased intracranial pressure with vigorous stimulation of the
airways, mechanical trauma to the trachea, and bacterial contamination.
- All patients should be preoxygenated with 100% oxygen for 1 to 2 minutes before suctioning.
- To reduce the risk of agitation, the patient should be informed before tracheal
suctioning is performed. The suctioning should be limited to 15 to 20 seconds. The
suction port on the catheter should be opened and closed intermittently and not closed for
more than 5 seconds at a time.
6. Continuous rotational therapy
- extends the practice of regular 2 hourly repositioning of patients from one side to the
other by placing the patient on a bed that moves to pre-programmed angles on a more
frequent basis or through the use of air mattresses that deflate alternatively from side to
side to provide the continuous postural position changes.
- Most studies on various patient populations demonstrate a lower incidence of
nosocomial pneumonia or atelectasis but no overall improvement in other clinically
significant outcomes such as duration of mechanical ventilation, length of stay in the
ICU, or mortality.
7. Assisted coughing
- Techniques include "huffing" in the setting of an open glottis where in expiration the patient
forcibly exhales quickly several times. Other maneuvers include abdominal or thoracic
compression on expiration to generate high intrathoracic pressures mimicking a cough.
8. Positive expiratory pressure therapy (PEP)
- involves the use of a facemask or mouthpiece that provides a resistance to airflow of 10
to 20 cm H2O on expiration. After repeating this maneuver a number of times, mucus in
the peripheral airways is mobilized and moved toward the larger airways to be coughed
or expelled with other techniques.
- Fiberoptic bronchoscopy has the advantage of providing direct visualization of the
airways and permits suctioning of specific segments where secretions may be retained,
causing problems such as atelectasis.
- Bronchoscopy can be considered as an adjunctive therapy for the treatment of atelectasis
or removal of secretions.
- Being an invasive procedure, bronchoscopy is not without risks, including complications
associated with sedation required for the procedure, transient increases in ICP, hypoxemia,
and hemodynamic consequences/arrhythmias.
- Atelectasis is a common complication encountered in the critically ill patient. This is often
secondary to prolonged supine body position and retained secretions obstructing airways.
- Lung expansion techniques mimic normal sigh maneuvers to help reverse and prevent
atelectasis and include:
(i) Deep breathing and incentive spirometry
(ii) Intermittent positive-pressure breathing
- The aerosolization of medications is an effective method for drug delivery directly to
lungs. The two most common methods of delivery are via nebulization or via metered-
dose inhalers (MDIs).
- The theoretical advantage of this form of therapy includes direct delivery and activity at
the site of pathology and the ability to deliver high concentrations with minimal systemic
absorption and toxicity.
- The most common aerosolized therapy is the administration of bronchodilators. Other
medications that can be administered directly to the lungs include corticosteroids,
antibiotics, antifungal agents, surfactant, mucolytic agents, and saline.
- the process of using a high flow of gas (usually 6 to 8 L/min) to produce small
respirable particles of the liquid medium containing the medication of interest.
- in the spontaneously breathing patient approximately 10% reaches the lower respiratory
tract/small airways. In mechanically ventilated patients, 1% to 15% is delivered to the
lower respiratory tract.
- pressurized canisters with the drug suspended in a mix of propellants, preservatives, and
- Factors that influence the efficacy of aerosol delivery in the mechanically ventilated patient include:
1. Position of administration in the circuit: the MDI should be closer to the endotracheal tube at the Y-piece
with a chamber, compared with a pneumatic nebulizer, which should be at least 30 cm from the Y-piece.
2. Humidification: this can decrease aerosol delivery to the respiratory tract because of greater deposition
in the ventilator circuit. Higher doses may be required to achieve the desired effect.
3. Timing of delivery: the aerosol should be delivered during the inspiratory phase to maximize drug delivery.
4. Flow rates: slower inspiratory flow rates (and therefore longer inspiratory time) increase delivery of nebulized
medications. A decelerating flow pattern can also increase delivery to the lower airways.
5. Tidal volumes: larger tidal volumes greater than 500 mL ensure optimal delivery.
6. Endotracheal tube size: tube sizes less than 7.0 mm reduce delivery.
7. Density of inhaled gas: low-density gases such as helium-oxygen mixtures increase deposition to the lower
airways by increasing laminar flow and producing smaller respirable particle size.
- Bronchodilators are the most frequently administered aerosolized therapy in the
critically ill patient and are generally well tolerated in the critically ill patient.
- In mechanically ventilated patients, the use of nebulization is either equally as good as or less effective
than an MDI with a spacer. MDI administration has the advantage of easier use without the risk of bacterial
contamination and need for adjustment of flow rates.
- Theoretical advantages of aerosolized antibiotics include direct therapy at the site of
infection at higher concentrations with a lower risk of systemic absorption and side effects.
- The role for aerosolized or instilled (via the endotracheal tube) antibiotics as an adjuvant for the prevention
or treatment of pulmonary infections in the ICU remains to be defined with better clinical studies.
- Induce bronchospasm and probably have no role
- Racemic epinephrine has been used as a therapy for acute upper airway obstruction secondary to inflammation
- Numerous clinical observational studies in ALI/ARDS have demonstrated
improvements in oxygenation by improving VQ mismatch as demonstrated by a
10% to 20% increase in PaO2/FIO2 ratio and a reduction on pulmonary vascular
resistance and mean pulmonary arterial pressures by at least 5 to 8 mm Hg.
- Nitric oxide was first described as a vascular-derived relaxing factor that caused
vasodilation via vascular smooth muscle relaxation. It is a highly lipid-soluble gas that
allows for rapid diffusion through the alveoli-blood barrier into the pulmonary circulation
and smooth muscle cells of the vasculature.
- The main action of NO is mediated by activating guanylate cyclase and increasing
intracellular cyclic guanylate monophosphate, thereby causing smooth muscle and
subsequent vasomotor relaxation.
- The beneficial effects observed with inhaled NO are mediated primarily through this
action on the pulmonary vascular smooth muscle. Pulmonary blood flow is specifically
increased in well-ventilated regions, which improves matching of perfusion to
- It also has anti-inflammatory effects
- Randomized controlled trials of varying sample size and design had similar findings.
Typically, NO improved the PaO2 and PaO2/FIO2 ratios acutely, but by 24 to 72 hours
those in the control group achieved the same level of improvement.
- Similarly, although a reduction in mean pulmonary artery pressure was also observed
in these trials with the use of NO, this did not translate into clinically meaningful outcomes
of a decrease in mortality, less organ failure, or days free of mechanical ventilation.
- Only 60% of ALI/ARDS patients respond to inhaled NO. No clear predictors of who
will respond to NO exist.
- Given that doses below 40 ppm were safe without any significant adverse effects, it
can be considered a "rescue" therapy to possibly allow for more protective forms of
ventilation with decreases in FIO2 and mean airway pressures to maintain acceptable
oxygenation or in situations in which secondary pulmonary hypertension leads to
compromised hemodynamic function from right ventricular failure
potential indications include:
- Inhaled NO is typically started at low doses ranging from 1 to 2 ppm and gradually
increased until the desired effect is achieved.
- One method, as recommended from the U.K. Consensus conference on NO use, is to
perform a dose response test starting at 20 ppm and reducing the doses to 10, 5, and 0
ppm to find the lowest effective dose. A significant response should be considered as a
20% increase in the PaO2/FIO2 ratio or at least a 5 mm Hg decrease in the mean
pulmonary artery pressure.
- The improvement in gas exchange is usually seen at lower doses. The dose required to
reduce mean pulmonary artery pressure is usually higher. The usual dose ranges from 10
to 40 ppm.
- Doses greater than 80 ppm are associated with a higher risk for adverse effects.
- Adverse effects of NO include:
(i) the formation of methemoglobin and
(ii) the spontaneous oxidation to nitrogen dioxide (NO2). NO2 is known to be toxic to the
respiratory system with maximal exposure limited to 5 ppm. Complications from NO2
exposure include airway irritation and hyperreactivity with levels as low as 1.5 ppm,
pulmonary edema, and pulmonary fibrosis when exposed to higher levels.
(iii) Rebound pulmonary: vasoconstriction can occur with sudden discontinuation leading
to rapid worsening of VQ mismatch and pulmonary hypertension with significant
of nitric oxide
- To reduce the risk of exposure to NO2, NO should be stored at concentrations no higher
than 1000 ppm in a pure nitrogen environment and only exposed to oxygen at the time of
- NO should be delivered into the ventilator circuit as close to the patient as possible.
- NO and NO2 levels should be monitored closely on the inspiratory side of the Y-piece
when using doses greater than 2 ppm.
to nitric oxide
- An absolute contraindication to NO therapy is methemoglobinemia reductase deficiency
(congenital or acquired).
- Relative contraindications include bleeding diathesis (secondary to reports of alteration
in platelet function and bleeding time with inhaled NO), intracranial hemorrhage, and
severe left ventricular failure (New York Heart Association grade III or IV).
- Inhaled prostaglandins I2 (PGI2) and E1 (PGE1) are alternative medications that have
effects similar to inhaled nitric oxide with minimal systemic effects.
- For PGI2, doses ranging from 1 to 25 ng/kg/min are favorably tolerated with similar
reductions in pulmonary artery pressures and improvements in oxygenation as inhaled NO.
- PGE1 has the advantage of a more rapid degradation by the pulmonary endothelial cells,
providing a selective advantage over PGI2 at higher doses.
- Additional studies are required to define a role for these agents, but they can be
considered as alternatives for rescue therapy for similar conditions treated with inhaled NO.
- Helium is an inert gas with a significantly lower density than room air (1.42 g/L for
oxygen versus 0.17 g/L for helium).
- By substituting helium for nitrogen in a helium-oxygen mix (heliox), the degree of reduction in density
of the gas is directly proportional to the fraction of the inspired helium concentration in the mix.
- Heliox reduces the Reynolds number and thereby results in more laminar flow, therefore reducing
airflow resistance, work of breathing, and dynamic hyperinflation associated with a high resistance.
- Clinical situations in which heliox may be used include conditions with high airflow
resistance such as severe acute exacerbations of asthma or COPD, bronchiolitis,
bronchopulmonary dysplasia, and extrathoracic or tracheal obstruction.
- Disadvantages of using heliox in critically ill patients include the cost of therapy and the high
concentrations of helium required. Most studies utilize helium:oxygen mixes of 80:20 or 70:30 to
achieve a therapeutic benefit. At higher concentrations of oxygen, the effect of helium is less and
therefore is limited in use to those not requiring high FIO2. Ventilators also require recalibration for
measured FIO2, flows, and tidal volumes when using heliox.
in sepsis &
- international guidelines recommend the use of low dose corticosteroids for the treatment
of septic shock. However, there are some discrepancies in these recommendations.
(i) the Surviving Sepsis Campaign recommended the use of stress dose of corticosteroids
for septic shock regardless of adrenal function.
(ii) the American College of Critical Care Medicine Task Force recommended that stress
dose of corticosteroids should be used only in refractory septic shock or in adrenal
of action of
- Cells from most tissues are responsive to corticosteroids, which freely cross cell
membranes. The glucocorticoids receptor forms an inactive intracytosolic complex with
chaperone proteins like heat shock protein (HSP) 40, HSP56, HSP70, and HSP90,
immunophillins, P23, and other unknown proteins
- The receptor contains three domains: one binds corticosteroids, one binds to DNA, also
involved in dimerization; and one activates the promoters within the genes.
- Binding of corticosteroids to the glucocorticoids receptor induces the release of
chaperone proteins and the dimerization of the complex, which then, enters into the
nucleus and interacts with specific binding sequences, the glucocorticoid responsive
- Subsequently, transcription of some genes (e.g.most cytokines, adhesionmolecules,
lipoxygenase, etc.) initiated by various transcriptional factors such as AP1, NF-AT and
NF-kB are prevented. In addition, glucocorticoids receptor dimers induce the inhibitor of
- Other GRE sites upregulate the transcription of numerous other genes (e.g. lipocortin-1,
- Physicochemical interactions occur in-between the cell's membrane and corticosteroids
inducing very rapid (within seconds), nonspecific, nongenomic effects.
- Some of these effects might be part of the host response to sepsis. For example, loss in
the corticosteroids physicochemical interaction with hypothalamic synaptosomes], may
partly explain the loss in circadian rhythm of cortisol synthesis during sepsis.
- non genomic effects of cortisol are thought to control immediate catecholamine release
from sympathetic cells. Such neural modulation by corticosteroids may explain the rapid
restoration of sympathetic modulation on heart and vessels, and may account for the
hydrocortisone induced rapid pressure sensitization to exogenous catecholamine in septic
- by interacting with NF-IL6, corticosteroids enhance the synthesis of the acute phase
reactants; with AP-1 and NF-kB, they inhibit the synthesis of various proinflammatory
- corticosteroids prevent the migration of inflammatory cells from circulation to tissues
by blocking the synthesis of various chemokines and chemotactic cytokines. They
prevent the synthesis of almost all proinflammatory cytokines including several
interleukins (interleukin-1, interleukin-2, interleukin-3, interleukin-6), interferon-g (IFN-
g), granulocyte macrophage colony stimulating factor, and tumor necrosis factor-a (TNF-
a). They also enhance the production of the macrophage migration inhibitory factor
- by stimulating the synthesis of lipocortin-1, corticosteroids inhibit the synthesis of
soluble phospholipase A2 (PLA2) and the subsequent arachidonic acid cascade, reducing
the production of leukotrienes, the main inflammatory mediators in humans.
- corticosteroids also inhibit the synthesis of inducible cyclooxygenase-2 (COX2) and of
inducible but not constitutive nitric oxide synthase (NOS).
- Chronic corticosteroid excess induces hypertension, whereas adrenal insufficiency
- corticosteroids regulate vascular responses to norepinephrine and angiotensin II, but not
to vasopressin. The underlying mechanisms remained unclear, and may involve multiple
pathways like iNOS and COX-2 inhibitions or the stimulation of the phosphoinositide
- in healthy volunteers, a 6-hour infusion of 3 mg/kg/min hydrocortisone, either immediately before or
concomitantly to endotoxin exposure, prevented LPS-induced fever, tachycardia, increase in plasma
levels of epinephrine, CRP, and TNF-a, but not interleukin-6.
- In septic shock, intravenous hydrocortisone (about 300 mg for 5 days) decreases core temperature,
heart rate, and plasma levels of PLA2 and C-reactive protein.
- In a French multicenter trial on low dose corticosteroids in septic shock, it was shown that the
systemic inflammatory response to sepsis, assessed by interleukin-6 levels, was significantly
altered by corticosteroids only in adrenal insufficient patients
- nonresponders (increment in cortisol of 9 mg/dl or less) to 250 mg of corticotropin. In that study,
the adrenal insufficient septic shock had higher TNFa, interleukin-6 and interleukin-8 levels than
- In another placebo-controlled, randomized trial, 41 patients with septic shock received 50mg bolus
followed by a continuous infusion of 0.18 mg/kg/h of hydrocortisone until shock reversal. In that study,
as compared with the placebo, interleukin-6 levels were also significantly decreased by hydrocortisone
infusion, whereas interleukin-10 levels remained unaltered.
- low dose of hydrocortisone has been shown to downregulate sepsis-associated overexpression of
the 'late' inflammatory mediator, MIF by peripheral blood monocytes
- In a recent randomized study, the acute vascular effects of hydrocortisone (200 mg intra-arterial over
3 hours) were investigated in healthy adult male volunteers. This study elegantly demonstrated that
hydrocortisone did not affect biochemical or physiologic markers of nitric oxide activity. Thus, one can
conclude that any early (within 3 h) vascular effect of hydrocortisone is not mediated through the NO
- In septic shock, several placebo-controlled randomized studies have reported the cardiovascular
effects of low dose of corticosteroids (about 200-300 mg/day) given for a prolonged period. These
studies consistently showed that corticosteroids increased systemic vascular resistance with little
effects on the cardiac index and pulmonary hemodynamics.
- trials consistently show that corticosteroids reduce the duration of shock. The
probability of being weaned from vasopressor at one week was greater in corticosteroid-
treated septic shock than in placebo-treated septic shock and the relative risk was 1.60
- Only three trials have subgroup analyses based on adrenal insufficiency. However, only two studies
used the same definition for adrenal insufficiency. In both of them, the favorable effects of corticosteroids
on shock reversal were observed only in the adrenal insufficient patients (nonresponders to corticotropin).
- In the first study of 300 patients with septic shock, the median time to weaning from vasopressors was
reduced by 3 days in the corticosteroid-treated adrenal insufficient patients compared with the placebo
group (P = 0.001), while there were no difference between corticosteroids and placebo in the responders
to corticotropin. In the second study, hydrocortisone significantly shortened the duration of shock (P = 0.02).
This effect was seen only in the adrenal insufficient septic shock (n=26; P=0.06), and not in the
responders to corticotropin (n = 15; P = 0.90).
- Confalonieri et al. have investigated the efficacy and safety of a 7-day treatment with intravenous
hydrocortisone (240 mg/day) in community-acquired pneumonia associated sepsis. In their study, treatment
with hydrocortisone significantly prevented onset of shock (P =0.001), reduced multiple organ dysfunction
score (P =0.003), hospital length of stay (P = 0.03), and in-hospital mortality (P = 0.009).
- In septic shock, evidence from five randomized trials suggested that prolonged treatment with
low dose corticosteroids reduced 28-day mortality (relative risk = 0.80, 95% confidence interval 0.67-0.95),
in-hospital mortality (relative risk = 0.83, 95% confidence interval 0.71-0.97), and ICU mortality (relative
risk = 0.83, 95% confidence interval 0.70-0.97). It is important, however, to note that one study accounted
for 70% of patients included in that meta-analysis. In this study, corticosteroids improved survival only in
adrenal insufficient septic shock.
- In a meta-analysis of all published randomized trials that evaluated the effects of high or low doses of
corticosteroids for short or long periods of time, there was no evidence for significant increases of
super-infection, gastroduodenal bleeding, or hyperglycemia.
- Corticosteroids could be a valuable treatment for septic shock, depending upon the way they are used.
- There is no evidence to support the use of short courses of high doses of corticosteroids in patients with
- Current evidence suggests that, in septic shock, one-week treatment with 200-300 mg of hydrocortisone
alleviates the symptoms of systemic inflammatory response, reduces the duration of shock, and
increases survival. Corticosteroids favorable effects on inflammation, hemodynamics, and survival
are more marked in patients with an increment in cortisol of 9 mg/dl or less after 250 mg of corticotrophin
(nonresponders or adrenal insufficient).
- The adrenal gland is a mixture of the steroid hormone-producing adrenal cortex and the
adrenal medulla, which is responsible for the secretion of catecholamines.
- The secretion of cortisol and aldosterone is controlled by different mechanisms,
whereby the pituitary axis (corticotropin-releasing hormone [CRH] or corticotropin) is
vital for cortisol secretion and the renin-angiotensin system is vital for aldosterone
- Cortisol regulates a wide variety of genes involved in energy metabolism
(eg, glucose-protein-fatty acid metabolism), mineral homeostasis, and immune
function and influences many more cellular functions.
- Aldosterone has a more focused action on mineral homeostasis
- Although adrenal insufficiency has been known as a clinical syndrome for a long time,
new risk groups have been identified, because as many as 20% of AIDS patients
eventually develop adrenal insufficiency. Moreover, patients with head trauma develop
pituitary insufficiency much more frequently than previously recognized.
- Primary and secondary adrenal insufficiency (excluding critical illness adrenal
insufficiency and adrenal insufficiency secondary to acute interruption of chronic
glucocorticoid therapy) are rare diseases, affecting less than 0.1% of the population
- usually present slowly over time with nonspecific symptoms of chronic fatigue,
weakness and lethargy, anorexia and weight loss, postural hypotension, abdominal
complaints (eg, nausea, vomiting, diffuse abdominal pain), and loss of libido as well as
loss of axillary and pubic hair in women.
- Hyperpigmentation (attributable to excess proopiomelanocortin and melanocyte-
stimulating hormone), especially of non-sunlight-exposed skin areas, is an imported
clinical hallmark for the attentive and suspicious physician.
- Abnormal serum electrolytes with low sodium, high potassium, and, occasionally,
hypercalcemia and fasting hypoglycemia, and especially this combination are highly
suspicious for adrenal insufficiency.
- Acute adrenal insufficiency (adrenal crisis) is mainly attributable to mineralocorticoid
deficiency; thus, the clinical presentation is dominated by hypotension or hypotensive shock.
- If adrenal insufficiency is confirmed or highly likely based on the acute screening
results, replacement therapy should be continued by the intravenous or intramuscular
route (at 150-300 mg/d for 2 to 3 days) until full clinical recovery. High dose cortisol
replacement has major mineralocorticoid effects therefore no additional mineralo-
corticoid therapy is needed in the acute phase.
- The 150- to 300-mg/d replacement dose of hydrocortisone is frequently considered to
be a physiologic stress dosage. However, serum cortisol levels measured after such so-
called ''acute replacement'' dosages exceed several times the maximal stress cortisol
levels found in healthy or even critically ill patients thereby questioning the need for
maintaining such high acute emergency replacement dosages.
- In contrast to the rather generous replacement dosage used in emergency situations, the
chronic replacement dosage for patients with adrenal insufficiency should be as low as
possible with clear instructions for dosage adjustments in case of stress or acute emergencies.
- Detailed information about and education of the patient and of his or her family and a
medical emergency alert card as well as appropriate follow-up should be initiated.
- adrenal insufficiency is a hormone deficiency syndrome attributable to primary adrenal
diseases or caused by a wide variety of pituitary-hypothalamic disorders.
- if such diseases evolve gradually over time, they rarely cause an abrupt-onset adrenal
insufficiency crisis, whereas acute destruction of the adrenal or pituitary gland or
acute interruption of glucocorticoid therapy is more likely to cause an acute onset
adrenal failure crisis.
- there is increasing attention to relative adrenal insufficiency in patients with acute
(nonadrenal or pituitary) critical illness. Such patients still secrete cortisol (and
corticotropin in the early phases of critical illness) but less than expected during acute
stress, and the survival of such patients can be improved by pharmacologic doses of