CKD , Dentists, anaesthetics, drugs etc

[Pendrag0n]

Just had to have a tooth out and they usually have to give me a double
dose of anaesthetic and I wondered what the clearance was like with
CKD, and found this interesting article.

Stuff I had was *septanest 1:100,000-articaine hydrochloride
4% with adrenaline (Epinephrine) whatever that means. I just know it
aint gonna be good news at stage 4 :(






Issue 18 (2004) Article 4: Page 1 of 1
http://www.nda.ox.ac.uk/wfsa/html/u18/u1804_01.htm
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CHRONIC RENAL FAILURE AND ANAESTHESIA

Dr Callum McDonald,
Dr Quentin Milner,
Royal Devon and Exeter Hospital, UK


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Introduction Neurological abnormalities
Fluid and electrolyte derangement Endocrine disturbances
Haematological abnormalities Altered drug handling in CRF
Cardiovascular and pulmonary abnormalities Conclusions
Immune function Further reading
Gastrointestinal abnormalities

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Chronic renal failure (CRF) and end stage renal disease (ESRD) are
functional diagnoses characterised by progressive decrease in
glomerular filtration rate (GFR). CRF occurs where GFR has been
reduced to 10% (20ml/min) of normal function and ESRD when GFR falls
below 5% (10ml/min). Patients with ESRD are dependant on renal
replacement therapy (RRT) to survive. The relationship between serum
creatinine and GFR is not linear (figure 1) and serum creatinine does
not rise until GFR has fallen below 50%. In addition, renal tubular
secretion of creatinine is increased at higher serum levels.



The incidence of ESRD in the developing world is difficult to estimate
and ranges from 40 per million population (pmp) to 340 pmp. The
prevalence of ESRD can be more accurately recorded as the number of
patients receiving RRT. It ranges from 100 pmp to 600 pmp and can be
related to a countries economic wealth. In comparison, the prevalence
in the United States of America (USA) is 1191 pmp.

Glomerulonephritis is the main cause of ESRD worldwide (11% - 49%).
Proliferative glomerulonephritis is more common in developing
countries and may be secondary to endemic infections like
streptococcus, schistosomiasis, and malaria. Focal segmental
glomerulonephritis is also common in Africa, while IgA nephropathy is
common in Asia and Pacific regions. Amyloidosis causes a smaller
proportion of glomerular disease and again may be as a result of
chronic endemic infections. Interstitial nephritis, secondary to renal
stones, obstruction of the urinary tract, tuberculosis and various
nephrotoxins, are responsible for up to 20% of ESRD. Diabetes mellitus
and hypertension remain important factors in the aetiology of ESRD,
but less so in the developing world than in the USA where they account
for around 65% of ESRD.

Patients with ESRD frequently manifest a wide range of pathological
organ dysfunction either caused by the primary disease such as
diabetes mellitus, the intrinsic pathological effects of uraemia or a
combination of the two. Uraemia refers to the effects resulting from
the inability to excrete products of the metabolism of proteins and
amino acids. Some of the toxic products of amino acid metabolism are
listed in table 1. The multi-organ effects of uraemia are also caused
by the impairment of the wide range of metabolic and endocrine
functions normally carried out by the kidney. This review will
concentrate on the more common pathophysiological changes encountered
of relevance to anaesthesia. Despite impressive medical development,
the overall 4 year survival for patients with ESRD in the UK is only
48%.

Table 1 Major identified uraemic toxins
Guanidine
Methlguanidine
Phenols
Guanidinosuccinic acid
Tyrosine
Myoinositol Benzoates
Creatine
Creatinine
Tryptophan
Aliphatic amines
Glucuronoconjugates


Fluid and electrolyte derangement

Sodium - In a normal individual more than 25,000 mmol of sodium ions
are filtered daily with less than 1% being excreted. CRF can therefore
be associated with sodium retention, sodium wasting or normal sodium
balance, and is further influenced by factors such as diuretic use and
cardiac function. Most patients however demonstrate a mild degree of
sodium and water retention whist the extracellular fluid volume
remains isotonic. Ironically, the patient with CRF also has impaired
renal concentrating mechanisms and thus extrarenal fluid losses such
as vomiting, diarrhoea or pyrexia may rapidly cause hypovolaemia and
hypotension.

Potassium - Adaptive processes increase potassium secretion in the
distal nephron (collecting tubules) and also in the gut. Whilst a wide
range of plasma potassium concentrations can be encountered, dependent
on factors such as diuretic use, it tends to be elevated. Acute
changes present the greatest threats to life. A range of drugs may
cause acute hyperkalaemia such as beta-blockers, potassium sparing
diuretics (spironolactone), angiotensin converting enzyme (ACE)
inhibitors or angiotensin antagonists, non-steroidal anti-inflammatory
agents and nephrotoxins such as aminoglycosides and cyclosporins.
Extracellular acidosis causes an exchange of intracellular potassium
for extracellular hydrogen ions in an attempt to maintain electrical
neutrality. In acute acidosis the serum potassium will rise 0.5mmol/l
for each 0.1 unit decrease in pH. For this reason hypercarbia should
be avoided during general anaesthesia.

The kidney handles magnesium in a similar way to potassium. Reduced
excretion may cause hypermagnesaemia, muscle weakness and potentiate
non-depolarising muscle relaxants.

Acidosis - Chronic metabolic acidosis is a common feature of ESRD. The
inability to secrete protons or buffers such as phosphate, or to
regenerate bicarbonate limits the clearance of hydrogen ions.
Furthermore reduction in glutamine utilisation reduces ammonia
production and secretion into the proximal tubule. Retention of
organic anions causes a progressive increase in the anion gap and a
further fall in plasma bicarbonate concentration. Although plasma
bicarbonate concentrations rarely fall below 12-15mmol/l there is
little reserve to counter acute acidosis caused by ketoacidosis or
sepsis.

Calcium, phosphate, parathormone and renal osteodystrophy - Total
plasma calcium concentration is reduced in CRF. Renal production of
calcitriol (1,25-(OH)2D3) declines causing decreased intestinal
absorption of calcium. Phosphate excretion is impaired as GFR falls
below 20ml/min and hyper-phosphataemia develops. As phosphate levels
increase, calcium phosphate is deposited in soft tissues such as skin
and blood vessels further lowering plasma calcium concentration.
Hyperphosphataemia also has a negative effect on 1-a-hydroxylase the
enzyme responsible for renal calcitriol production. Both hypocalcaemia
and hyperphosphataemia are potent stimuli to parathormone secretion,
leading to hyperplasia of the parathyroid gland, and secondary
hyperparathyroidism. This causes increased osteoclast and osteoblast
activity causing osteitis fibrosa cystica. Patients usually tolerate
hypocalcaemia remarkably well, as long as oral calcitriol is
prescribed and calcium carbonate is used both as an intestinal
phosphate binder and a source of calcium. The interrelationship
between calcium, phosphate and parathormone in CRF is shown in figure
2.



Careful assessment of the pre-operative fluid and electrolyte status
is needed. Dehydration can cause further renal impairment and some
patients may benefit from pre-operative intravenous saline while
fasting. Patients with oliguric ESRD usually have a fluid restriction
imposed. This should be enough to cover insensible losses in addition
to their urine volume. When planning fluid requirements the patient's
normal daily fluid allowance should be considered and potassium
containing fluids should be avoided. Hourly urine volume measurement
and central venous pressure monitoring may be necessary
pre-operatively. Blood pressure should be kept within the patient's
normal range to maintain renal perfusion.

Patients awaiting dialysis may be hypervolaemic, and those recently
dialysed may be hypovolaemic. A period of 4-6 hours should ideally
elapse before anaesthesia to allow fluid compartment equilibration and
the clearance of residual heparin. Vascular instability may complicate
induction of anaesthesia. Indications for emergency pre-operative
dialysis include:

Hyperkalaemia (K+ > 6.0 mmol/L)
Fluid overload and pulmonary oedema
Metabolic acidosis
"Uraemic" toxicity and coma
Haematological abnormalities

A normochromic normocytic anaemia is a common finding in CRF.
Decreased renal erythropoietin production reduces stem cell
transformation into erythrocytes, while uraemic toxins reduce red cell
life. Chronic upper GI tract losses and those from dialysis further
compound the problem. Dietary deficiency in iron and folate also
occurs. The introduction in 1989 of synthetic erythropoietin has
revolutionised the management of anaemia in these patients, but a
compensated relative anaemia is still to be expected. Rapid increases
in haemoglobin concentration above 10g/dl often worsen hypertension
and may precipitate heart failure. Compensatory mechanisms increase
2,3-diphosphoglycerate production and move the oxyhaemoglobin
dissociation curve to the right thus enhancing oxygen delivery to the
tissues.

Coagulopathy. Patients with CRF have a tendency to excess bleeding in
the perioperative period. Standard tests of coagulation are usually
normal (prothrombin time/INR, activated partial thromboplastin time)
and platelet count is within normal limits. Platelet activity is
however abnormal with decreased adhesiveness and aggregation, probably
caused by inadequate vascular endothelial release of a von Willebrand
factor/factor VIII complex, which binds to and activates platelets.
Increased platelet release of b-thromboglobulin and vascular
production of PGI2 also contribute to the coagulopathy. Defects in
platelet adhesion may also be related to excessive nitric oxide (NO)
production. The plasma from patients with CRF has been shown to be a
potent inducer of endothelial NO production.

If it is measured, bleeding time may be prolonged beyond the normal.
Platelet dysfunction is not corrected by platelet transfusion, but if
operative bleeding occurs, it can be improved by dialysis. Rapid
improvements in coagulation require the use of cryoprecipitate or
DDAVP (which enhances release of von Willebrand factor). DDAVP
(0.3mcg/kg) is effective within 1-2 hours but has a short duration of
only 6-8 hours, and is subject to tachyphylaxis. Intravenous
conjugated oestrogens have a slower onset but a longer duration of
action (5-7 days). The risks of bleeding complications should be
considered when deciding to use regional anaesthetic techniques in
CRF.

Cardiovascular and pulmonary abnormalities

Cardiovascular abnormalities are very common in CRF, and represent 48%
of the causes of death in these patients. Systemic hypertension is the
most common with an incidence approaching 80%, although it is often
not a feature of sodium-wasting nephropathies such as polycystic
kidney disease or papillary necrosis. Plasma volume expansion
resulting from sodium and water retention is the most frequent cause
of hypertension, and may be significantly improved by dialysis. Some
patients may require beta-blockers, ACE inhibitors, alpha-blockers and
vasodilators to adequately control their blood pressure. Alteration in
the control of renin and angiotensin secretion may also contribute to
hypertension in 30% of patients.

Ischaemic heart disease (IHD) is a frequent cause of mortality in
patients with CRF. The incidence varies with patient subgroup, for
example it is present in 85% of diabetics older than 45 years with
CRF. Accelerated atherosclerosis results from decreased plasma
triglyceride clearance, hypertension and fluid overload causing left
ventricular hypertrophy and failure. The elevation in plasma
triglyceride levels is caused by a defect in lipoprotein lipase
activity and reduced lipolysis.

The incidence of metastatic calcific valvular heart lesions is
increased. Aortic valve calcification occurs in up to 55% of patients,
with aortic stenosis being present in 13%. Mitral valve calcification
occurs in 40% (stenosis 11%). Elevation in the calcium/phosphate
product and parathyroid hormone concentrations are the main cause. As
a result of these lesions, bacterial endocarditis is much more common
in dialysis patients than the normal population. Haemorrhagic uraemic
pericarditis was often seen prior to the advent of effective dialysis,
but is now uncommon and occurs in patients on inadequate dialysis
regimen. If untreated, it may progress to pericardial tamponade with
hypotension, elevated jugular venous pressure and signs of falling
cardiac output. Pericardectomy may be required but should be reserved
for those who fail to improve with immediate dialysis. Sudden death
from acute cardiac arrhythmias is frequent and related to both IHD and
electrolyte abnormalities.

Pulmonary complications are common in patients with CRF in the
postoperative period. Fluid overload, malnutrition, anaemia, impaired
humoral and cellular immune function and decreased surfactant
production predispose patients to atelectasis and infection.

Immune function

Sepsis is a leading cause of death in patients with CRF. Inhibition of
cell mediated immunity and humoral defence mechanisms occurs, with
little improvement following the instigation of dialysis. There is an
increased production of pro-inflammatory cytokines suggesting that
activation of monocytes may play a role in uraemic immune dysfunction.
Superficial infections are common in fistula and catheter sites, and
wound healing is poor.

The incidence of viral hepatitis B has decreased somewhat following
the introduction of erythropoietin and hepatitis B vaccination. There
is also an increased incidence of hepatitis C infection in patients on
haemodialysis and although there is often little effect on liver
function it is of concern in patients undergoing renal transplantation
and immunosuppression. Hospital staff must take precautions against
blood borne viruses in these patients.

Gastrointestinal abnormalities

Gastrointestinal abnormalities are frequent with anorexia, nausea and
vomiting contributing to malnutrition. Urea is a mucosal irritant and
bleeding may occur from any part of the GI tract. Gastric emptying is
delayed, residual volume increased and pH lowered. Peptic ulcer
disease is common and most patients will receive proton pump
inhibitors. The use of a rapid sequence induction technique needs be
balanced against the risks of difficult intubation in chronically ill
patients with poor dentition. Suxamethonium will increase the plasma
potassium concentration by approximately 0.5mmol/L and this is not
reliably prevented by precurarisation with a non-depolarising agent.
Patients with diabetes mellitus have an increased incidence of
difficult intubation and autonomic gastric paresis even in the absence
of CRF. In practice, rapid sequence induction is restricted to
patients who are inadequately fasted or have symptoms of gastric
reflux and a low serum potassium.

Neurological abnormalities

Many patients with CRF have abnormalities in central (CNS) and
peripheral nervous system function. CNS changes have a wide spectrum
from mild personality alterations to asterixis, myoclonus,
encephalopathy and convulsions. Peripheral neuropathy is common in
advanced stages of the disease and is initially a distal "glove and
stocking" sensory loss progressing later to motor changes. Both
dialysis and renal transplantation may improve the neuropathy. The
presence of a peripheral neuropathy should alert the anaesthetist to
the presence of an autonomic neuropathy with delayed gastric emptying,
postural hypotension and silent myocardial ischaemia. Two types of
neurological disturbances are unique to patients on dialysis. Dialysis
dementia with dyspraxia, myoclonus and dementia occurs in patients on
dialysis for many years and may be related to aluminium toxicity. The
dialysis disequilibrium syndrome is associated with rapid initial
reduction in plasma urea levels at the commencement of dialysis.

Endocrine disturbances

Changes in parathyroid function and lipid clearance have been noted
above. Glucose tolerance is impaired, but there is a reduced
requirement for exogenous insulin in diabetics, probably related to
the reduced metabolism of insulin by the failing kidney. Patients with
CRF have abnormalities of temperature regulation with reduced basal
metabolic rate and a tendency to hypothermia. This may be important
when assessing fever.

Altered drug handling in CRF

A wide range of pharmacokinetic changes occurs in drug handling in
patients with CRF. The volume of distribution is usually decreased,
but may be increased if there is fluid retention. Hypoalbuminaemia and
acidosis increase the free drug availability of highly protein bound
drugs. These changes may require an alteration in the loading dose of
a drug. The doses of benzodiazepines and thiopentone may need to be
reduced by 30% - 50%. Although the pharmacodynamics of propofol are
unchanged in CRF and the metabolites lack sedative activity, changes
in volume of distribution and mental state mean that a reduction in
induction dose may also be appropriate. The elimination of highly
ionised, water soluble drugs such as gallamine or atropine are
partially or completely dependent on renal excretion and may be
markedly reduced. However the duration of action of a single loading
dose will be dependent on redistribution rather than excretion.
Dialysis can only partially compensate for the loss of excretory
ability of the kidney.

Most lipid soluble analgesics are metabolised by the liver to water
soluble metabolites for renal excretion. Some of these metabolites may
have far greater activity than the parent drug. Morphine is
metabolised to morphine-6-glucuronide, a more potent analgesic and
respiratory depressant. The interval between doses will need to be
increased because of its reduced renal clearance. Metabolism of
pethidine produces norpethidine, which can cause seizures. Although
fentanyl undergoes hepatic metabolism and is not thought to have
active metabolites, its clearance is decreased in severe uraemia.
Alfentanil can be used as normal.

The elimination of volatile anaesthetic agents is not dependent on
renal function and their activity is unaffected by CRF. The hepatic
metabolism of both enflurane and sevoflurane will theoretically
produce nephrotoxic fluoride ions and their use should be discouraged
for prolonged durations. Metabolism of halothane produces fluoride
ions when the liver is hypoxic but has been used safely in patients
with renal disease. It has a greater myocardial depressant effect and
causes more arrhythmias than other inhalational agents and caution
should be observed when used in CRF patients with cardiovascular
impairment. Isoflurane, although more expensive, may be the agent of
choice as it undergoes less metabolism to fluoride ions. Nitrous oxide
has little effect on the kidney. Older agents such as cyclopropane,
ether and tricloroethylene are not recommended as they cause renal
vasoconstriction.

Atracurium and cisatracurium are obvious choices for muscle
relaxation. Around 90% is metabolised by ester hydrolysis and Hofmann
elimination. Plasma cholinesterase activity is not thought to be
affected by CRF and therefore mivacurium and suxamethonium (in the
absence of hyperkalaemia) may be used. Limited doses of vecuronium and
rocuronium are acceptable alternatives. Acidosis prolongs the action
of all muscle relaxants except gallamine. The excretion of
anticholinesterases and anticholinergic agents will be prolonged as
they are highly ionised and water soluble.

Local anaesthetics are valuable agents for peri-operative pain control
in CRF, but their duration of action is reduced secondary to acidosis.
Maximum doses of local anaesthetics should also be reduced by 25%
because of reduced protein binding and a lower CNS seizure threshold.

Non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided in
patients with CRF. NSAIDs inhibit the production of renal
prostaglandins PGE2 and PGI2, which are responsible for maintaining
renal blood flow during hypovolaemia and in the presence of
vasoconstrictors, and could precipitate acute renal failure.

Conclusions

The incidence of chronic renal failure is increasing throughout the
world. The effects of CRF are multiple and widespread beyond the
confines of the kidney. The function of many organ systems of great
interest to anaesthetists are adversely affected by a range of
accumulated toxins. Great improvements in nephrology and
transplantation mean that many more patients with CRF are living much
longer. Their appearance on both renal and unrelated operating lists
will continue to increase.

Further reading

Winearls CG (2003). Chronic Renal Failure. In Oxford Textbook of
Medicine (4th Ed) (eds. Warrell, Cox, Firth). Oxford University Press,
Oxford.
Hunter J (1995). Anaesthesia for the Patient with Renal Disease. In A
Practice of Anaesthesia (6th Ed) (eds. Healy & Cohen), pp. 752-768.
Edward Arnold, London.
Barsoum RS (2002). Overview: End-Stage Renal Disease in the Developing
World. Artificial Organs, 26(9):737-746.





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