Renal effects of inhalational anaesthetic agents

[SH4:p69]

Generic effects

• All inhalational anaesthetic agents produce similar dose-related:
  * Decrease in renal blood
  * Decrease in GFR
  * Decrease in urine output
• Prevented or lessened by preoperative hydration
• Due to effects of inhalational anaesthetic agents on BP and cardiac output

Fluoride-induced nephrotoxicity

• First recognised with methoxyflurane
  * Extensive metabolism (70%)
  * No renal effect when [F-]< 40microm/L
  * Subclinical when [F-] = 50-80
  * Clinical toxicity when [F-] > 80
• Fluoride level alone is not an indicator for fluoride-induced nephrotoxicity
  * Lack of toxicity when [F-] >50 with ENF and sevoflurane
• Fluoride interferes with enzymes in both proximal and distal tubules
• Risk factor for enflurane nephrotoxicity (??? also true for other fluoride-induced nephrotoxicity)
  * Enzyme induction
  * Obesity
  * Preexisting renal dysfunction

Symptoms and signs of fluoride-induced nephrotoxicity

• Polyuria
  * High output failure
  * ADH resistant [Edgar
• Hypernatremia
• Hyperosmolarity
• Increased plasma creatinine
• Inability to concentrate urine

Sevoflurane

• Has not been shown to cause renal impairment
  * Despite peak plasma fluoride consistently higher than enflurane

Possible explanation

• Intrarenal production of inorganic fluoride is more important for nephrotoxicity than hepatic metabolism
• Plasma fluoride level is related to hepatic metabolism
• Methoxyflurane and enflurane undergoes greater intrarenal metabolism

Vinyl halide nephrotoxicity

(i.e. compound A nephrotoxicity)

• Sevoflurane reacts with carbon dioxide absorbents containing KOH and NaOH
  --> F+ and H+ removed
• A few degradation products produced
  * Highest level is compound A (fluoromethyl-2,2-difluro-1-(trifluoromethyl) vinyl ether)

Compound A

• Compound A is a dose-dependent nephrotoxin in rats
  --> Causes proximal tubular injury at 50 to 100ppm
  * LD50 in rats is 400pm for 3 hours
• Production of compound A is higher when Baralyme is used
  * Probably due to higher absorbent temperature than soda lime
• So far, it has not been demonstrated that compound A causes in human impairment of urine concentrating ability and plasma creatinine level.

Concentration of compound A in the circuit

• At 1L/min, 19.7 ppm
• At 3L/min, 8.1 ppm
• At 6L/min, 2.1 ppm

Fresh gas flow of 2L/min is supposed to limit the concentration of compound A in the circuit

Probenecid

• Selective inhibitor of organic anion transport
• Prevents compound A-induced renal injury in rats

Mechanism of renal injury

• Metabolism of compound A to a reactive thiol
  * Via the beta-lyse pathway
• Human has less than 1/10 of the enzymatic activity in this pathway than rats

Halothane

• Halothane also react with CO2 absorbent to form degradation products that are nephrotoxic to rats
• But the product is les nephrotoxic than compound A