Martin R. Tramèr Dept Anästhesie, Klinische Pharmakologie & Intensivmedizin

Universitätskliniken & Medizinische Fakultät Genf - Schweiz

Deutscher Anästhesiecongress 2010

PARACETAMOL, DEXAMETHASONE UND NSAR – EINE GEFAHR FÜR DIE KINDER?

2 4 6 8 10 12 14 16 18 20 Number needed to treat

636 Diclofenac 50mg 257 Naproxen 440mg 2898 Ibuprofen 400mg 946 Morphine 10mg IM 816 Paracetamol 650mg/codeine 60mg 963 Paracet 650mg/dextroprop 65mg 5061 Aspirin 650mg 2283 Paracetamol 1000mg 882 Tramadol 100mg 1167 Paracetamol 650mg 440 Dextropropoxyphene 65mg 1305 Codeine 60mg

NTTs for ≥50% pain relief over 4-6h in patients with moderate to severe pain

McQuay & Moore Evidence-Based Resource in Pain Relief, Oxford University Press 1998

Paracetamol

Anesthesiology 2005;103:1296-1304

Paracetamol - Morphine sparing

Morphine consumption in controls: Δ 50 mg/24h

Paracetamol - Pain intensity

Elia et al. Anesthesiology 2005;103:1296-1304

Pain intensity in controls: Δ 4/10 at 24h

Morphine-related adverse effects

Elia et al. Anesthesiology 2005;103:1296-1304

Remy et al. BJA 2005;94:505-13

No impact on the risk of PONV No impact on the risk of sedation No impact on the risk of urinary retention

RCT: 107 young adults undergoing TE under LA (lidocaine + epinephrine)

Prior to surgery: iv single dose of

75 mg diclofenac 3 g paracetamol Placebo

Acta Anaesth Scand 2007;51:1147-54

Silvanto et al. Acta Anaesth Scand 2007;51:1147-54

Plac

Diclo

Para

Plac

Diclo

Para

Plac

Diclo

Para

Silvanto et al. Acta Anaesth Scand 2007;51:1147-54

Aspartate aminotransferase

Alanine aminotransferase

Glutathione transferase

NEJM 1997;337:1112-7

Hepatic coma Death

7 (33%) 4 (19%)

3 (6%) 1 (2%)

0.006 0.04

Acetaminophen ingestion accounted for 12% of all patients hospitalized with overdoses and 40% of patients with acute liver failure

Watkins et al. JAMA 2006;296:87-93

BMJ 2000;321:1460-3

NSAIDs Cox-2 inhibitors

NSAIDs & surgery - PROs

•  Analgesic •  Multiple routes of administration

- po, pr, iv, sc, im, transcutaneous •  Non-opioid

- Opioid sparing effect - Prevention of opioid adverse effects

nausea & vomiting, pruritus, urinary retention, sedation,

respiratory depression - No legal constraints for prescription - No “opioid fear”

NSAIDs & Coxibs - Morphine sparing

Morphine consumption in controls: ± 50 mg/24h

Anesthesiology 2005;103:1296-1304

Anesthesiology 2005;103:1296-1304

Pain intensity in controls: ± 4/10 at 24h

NSAIDs & Coxibs – Decrease in pain intensity

Elia et al. Anesthesiology 2005;103:1296-1304

NNT≈15

Morphine-related adverse effects

•  Suppression of cyclooxygenase-mediated thromboxane A2

synthesis

- Block of endogenous prostaglandine synthesis

- Inhibition of platelet aggregation

- Renal dysfunction

- GI

•  Allergic reactions

•  Hepatic failure

Toxicity with acute NSAID usage

Anesthesiology 2005;103:1296-1304

Anesthesiology 2005;103:1296-1304

NEJM 2005;352:1092-102

NNH 33

BMJ 2006;333:519

Allford et al. Ped Anesth 2009;19:145-52

Cochrane Database Sys Rev 2005;2:CD003591

8/497 (1.6%) 5/458 (1.1%) NNH ± 200 1.46 [0.49, 4.40]

4/40 0/20 4.86 [0.57, 41]

1.88 [0.71, 5.01] 12/522 (2.3%) 5/463 (1.1%) NNH ± 80

“NSAIDs did not cause any increase in bleeding requiring a return to theatre.”

6 RCTs 540 patients 13 bleedings

Anesth & Analg 2003;96:68-77

NNH 60

Reoperation

Anesthesiology 2003;98:1497-502

Reoperation

0.8% ⇒ 4.2% NNH 30

Dexamethasone

Anesth & Analg 2000;90:186-94

BJA 2006;97:593-604

Dose-responsiveness? •  for PONV? •  for analgesia? Adverse effects?

Otolaryngol Head & Neck Surg 2006;134:181-6

Czarnetzki et al. JAMA 2008;300:2621-30

RCT, dose-finding, placebo-controlled, double-blind

Measurements •  During 24 hours hospitalisation •  7 day questionnaire at home •  ENT control after 10 days

Eligibility •  Age 2-16 years •  Elective tonsillectomy (+/- adenotomy) •  No bleeding history, no aspirin intake

Intervention •  Dexa 0.05, 0.15, or 0.5 mg/kg (max. 20 mg), or placebo IV before surgery •  4 x 80 = 320 children

Trial was stopped early for safety reasons N = 215 children

Czarnetzki et al. JAMA 2008;300:2621-30

Dose-responsiveness for PONV

44%

12% NNT ± 3

Czarnetzki et al. JAMA 2008;300:2621-30

NSAID sparing effect

65%

40% NNT ± 4

Czarnetzki et al. JAMA 2008;300:2621-30

8 children needed a reoperation: PLAC 0 versus DEXA 8

Increased risk of bleeding (despite NSAID sparing)

15 children (68% of those bleeding) had a bleed ≥24h

22 children had a bleed: PLAC 2 versus DEXA 20

ANZ J Surg 2007;77:579-82

Retrospective case note review (n=4,546)

NON-OPIOID ANALGESIA: PARACETAMOL, NSAID, DEXAMETHASONE

Paracetamol

Weak analgesic No opioid-sparing No anti-inflammatory effect CAVE: Hepatotoxicity

NSAIDs

Strong analgesics Some opioid-sparing CAVE: Renal toxicity CAVE: Bleeding tendency

Coxibs Strong analgesics Some opioid-sparing CAVE: Renal toxicity

Dexamethasone

Weak analgesic Some NSAID-sparing Strong antiemetic CAVE: bleeding tendency