For patients more than 20% overweight, use ideal body weight. Children prefer elixir to cap sules or tablets. It is important to note that elixir formulation is available in di \200 erent formulation strengths when prescribing the dose by volume. Proprietary cough and cold medications containing acetaminophen are also available. Concurrent use of such medication s can result in inadvertent acetaminophen toxicity. Th e relative bioavailability of rectal formulations is reduced out of the neonatal period and dose can be increased by 30%. Dose is reduced in premature neonates (e.g. 24 and 45 mg/kg/d at 30 and 34 weeks postmenstrual a ge, respectively. Serum concentration E \200ect compartment concentration Pain Score (A) ketorolac (0.75 \200\2231 g/kg) to morphine (0.1 mg/kg) for analgesia aft er pediatric tons illectomy, strabismus surgery, or general sur- gery have demonstrated similar degrees of an algesia with reduced emesis with some increased bleeding in children given ketorolac. Diclo fenac and ketorolac reduce morphine use by up to 40% in children aft er a surgical insult. 10 14 ) 0 1 \200\223 0 S A V ( e r o c s n i a P ) L / g m 12 8 10 ( n o i t a r t n e c n o C 6 8 6 4 Confl icting reports plague the literature as to whether NSAIDs or acetaminophen display gr eater analgesic eff ect when given alone. An early meta-analysis comparing single doses of acetaminophen 7 to 15 mg/kg with ibuprofen 4 to 10 mg/kg found similar analgesic eff ect in children (Perrott et al., 2004 ). A more recent meta-analy- sis identifi ed 54 studies dir ectly comparing the analgesic eff ect of acetaminophen with ibuprofen (Pierce and Voss, 201 0 ). Th e authors concluded that ibuprofen is at least as eff ective as, if not more so tha n, acetaminophen in both adults and children. Th ese compari- sons are diffi cult to interp ret because of diff erences in pain insult, timing of response, duration and nature of pain scores, patient ages, doses administered, and formulations used (Anderson, 2004 ). 4 2 2 0 0 0 2 4 6 8 10 Time (h) (B) 10 20 ) 0 1 \200\223 0 S A V ( e r o c s n i a P ) L / g m 8 15 ( n o i t a r t n e c n o C 6 10 4 Plasma concentration E \200ect compartment concentration Pain Score NSAIDs appear to be equally eff ective at commonly used doses (Davies and Skjodt, 2000 ). I t has been suggested (Maunuksela and Olkkola, 2003 ) that 1 mg/kg of rectal diclofenac = 10 mg/kg of oral ibuprofen = 40 mg/kg of rectal acetaminophen = 5 mg/kg of IV ketoprofen = 0. 5 mg/kg of IV ketorolac. A single dose of ibuprofen 400 mg had a NNT of 2.5 for at least 50 % pain relief compared with placebo (Collins et al., 2002 ; Kopacz and Bernards, 2001 ). Th is means that two of every fi ve adults with pain of moderate to severe intensity will exp erience at least 50% pain relief with ibupro- fen, which they would not have had with place bo. Th e equivalent NNTs for ibuprofen 200 and 600 mg were 3.3 and 2.4, respectively, and t hose for diclofenac 25, 50, and 100 mg were 2.6, 2.3, and 1.8, respectively ( Table 43.3 ). 5 2 0 0 0 2 4 6 8 10 12 Time (h) Figure 43.7 (A) Th e temporal relationships for plasma concentration, e \200 ect compartme nt concentration and analgesic e \200 ect after 12.5 mg/kg acetaminophen elixir in a child . Th e absorption half-time used was 4.5 min. (B) Th e temporal relationships for plasma co ncentration, e \200 ect compartment concentration and analgesic e \200 ect after 20 mg/kg acetaminophen suppository in an adult. Maximum e \200 ect lags an hour behind the 4 h pea k concentration. Reproduced with permission from I. A. Gibb and B. J. Anderson, Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration, Archives of Disea se in Childhood , Volume 93, Issue 3, pp. 241 \200\223247, Copyright 2008 BMJ Publishing Group Ltd and Royal College of Pediatrics and Child Health, http://adc.bmj.com/. NSAID concentration \200\223response relationships are rare in chil- dren, but have been de scribed for adults. Data from adults given CHAPTER 43 the non-steroidal anti-inflammatory drugs and acetaminophen 441 Table 43.2 Classi \201 cation of common NSAIDs Table 43.3 Number needed to treat (NNT) for ibuprofen and diclofenac in adults Sulphonanilides Fenamic acid derivatives Selective COX-2 inhibitors Ibuprofen (mg) NNT (95% CI) Diclofenac (mg) NNT (95% CI) Nimesulide Mefenamic acid Etoricoxib 50 4.7 (3.3 \200\2238) 25 2.6 (2.2 \200\2233.3) Meclofenamic acid Paracoxib 100 4.3 (3.2 \200\2236.4) 50 2.7 (2.4 \200\2233) Salicylic acid derivatives Tofenamic acid Celecoxib 200 2.7 (2.5 \200\2233) 100 2.3 (2 \200\2232.5) 400 2.5 (2.4 \200\2232.6) Aspirin Flufenamic acid 600 2.7 (2.0 \200\2234.2) Acetic acid derivatives Sodium salicylate 800 1.6 (1.3 \200\2232.2) Propionic acid derivatives Etodolac Di \202 unisal Source: data from Derry, P., Derry, S., Moore, R. A., and McQuay, H.J., Single dose oral di clofenac for acute postoperative pain in adults, Cochrane Database of Systematic Reviews 20 09, Issue 2, Copyright 2009 Th e Cochrane Collaboration and Derry, C. J., Derry, S., Moo re, R. A., and McQuay, H. J., Single dose oral ibuprofen for acute postoperative pain in ad ults, Cochrane Database of Systematic Reviews 2009, Issue 3, Copyright 2009 Th e Cochran e Collaboration. Fenoprofen Indomethacin Enolic acids Ibuprofen Sulindac Meloxicam Flurtiprofen Ketorolac Phenylbutazone Ketoprofen Diclofenac Piroxicam Naproxen Tenoxicam Dexketoprofen compound. Approximately 20% of the parent drug is processed to this metabolite. Despite the impact of this metabolite, there are rea- sonable data to support the contention that dicl ofenac 50 mg is as eff ective as diclofenac 100 mg in adults (McQuay and Moore, 1998 ; Wong and Baker, 1988 ). Little or no information on developmental diff erences in arachidonic a cid release, prostaglandin formation, or COX-2 expression is available for the pediatric po pulation. It has been assumed that attaining similar adult exposure to 50 mg in children sh ould give similar eff ectiveness. Th is argument has been used to support a single dose of diclofenac 0.3 mg/kg for IV, 0.5 mg/ kg for suppositories, and 1 mg/kg for oral diclofenac in children aged 1 to 12 years (Standing et al., 2011 ). Phospholipids Phospholipase A2 Inhibited by steroids Arachidonic acid +lysophospholipids Cyclooxygenase Inhibited by NSAIDs PGH2 Peroxidase Pharmacokinetics Pharmacokinetic age-related changes and covariate eff ects are poorly docu mented for many of the NSAIDs. Th ere are limited data in infants less than 6 months age (L italien and Jacqz-Aigrain, 2001 ). NSAID formulations may be administered orally, topically , intraoc- ularly, intra-articularly, intravenously, intramuscularly, and rectally. NSAIDs are rapidly absorbed in the GI tract aft er oral adminis- tration. Time to maximal concentr ation is generally 1 to 2 h, but depends on formulation and concomitant food intake. Absorp tion due to the dissolution time of diclofenac tablets is slower than that associated with eff ervescent or liquid formulations (Standing et al., 2011 ). An absorption lag time of 1 h has been reported in children given enteric-coated diclofenac tablets (Romsing et al., 20 01 ). Th e relative bioavailability of oral preparations approaches 1 compared to IV admini stration. Th e rate and extent of rectal absorption of NSAIDs such as ibuprofen, diclofenac , fl urbiprofen, indomethacin, and nimesulide is generally less than those by oral routes. PGG2 PGF2a reductase TXA2 synthetase PGI2 synthetase PGE2 synthetase TXA2 PGF2a PGI2 PGE2 Figure 43.8 Th e conversion of arachidonic acid to PGG 2 , the precursor of the prostagland ins is controlled by prostaglandin H 2 synthetase (PGHS). PGHS comprises of two sites; a cy clooxygenase (COX) site and a peroxidise (POX) site ibuprofen aft er dental extraction suggest a similar E max to that described for acetaminop hen (1.54 of a scale 0 \200\2233; Li et al., 2012 ). Th e equilibration half-time (T 1/2 ke o) of 28 min was less than the 53 min reported for acetaminophen (Anderson et al., 2001 ). In addi- tion, the slope of the concentration \200\223response curve was steeper than that for acetaminophen (Hill = 2 for ibuprofen, Hill = 1 for acetaminophen) indicating a more ra pid onset of analgesia. Data from adult patients given ketorolac for postoperative pain rel ief aft er orthopedic surgery revealed an E max of 8.5/10 (VAS 0 \200\22310) and T 1/2 keo 24 min (Mandema and Stanski, 1996 ). Th e apparent volume of distribution ( V / F ) is small in adults (less than 0.2 L/kg, sugg esting minimal tissue binding) but is larger in children; for example, ketorolac V / F in c hildren 4 to 8 years old is twice that of adults (Forrest et al., 1997 ; Olkkola and Maunuk sela, 1991 ). Premature neonates (22 to 31 weeks gestational age) given IV ibuprofen had a V / F of 0.62 (SD 0.04) L/kg (Aranda et al., 1997 ). A dramatic reduction in ibuprofen cent ral volume following clo- sure of the PDA in premature neonates (0.244 versus 0.171 L/kg) i s reported (Van Overmeire et al., 2001 ). Interpretation of analgesia is also complicated by active metabo- lites. Naproxcinod is an active metabolite of naproxen (Ingelmo and Fumagalli, 2005 ). Diclofenac \200\231s 4 \200 -hydroxyl metabolite has 30% of the anti-infl ammatory and antipyretic activity of the par ent SECTION 6 pharmacological interventions 442 Th e NSAIDs, as a group, are weakly acidic, lipophilic, and highly protein bound. Th e boun d fraction in children and premature neonates is slightly lower than in adults. Th e impact of this reduced protein binding is probably minimal with routine dosing because NSAIDs cle ared by the liver have a low hepatic extraction ratio and they have a long equilibration ti me between plasma and eff ect com- partments (Benet and Hoener, 2002 ). Th ere is relativel y little trans- fer from maternal to fetal blood. Excretion of NSAIDs into breast milk of l actating mothers is low. that have increased potency and reduced side eff ects (Fiorucci and Distrutti, 2011 ). Drug interactions High protein binding among the NSAIDs has been used to explain drug inter actions with oral anticoagulant agents, oral hypoglycae- mics, sulphonamides, bilirubin, an d other protein-bound drugs. Warfarin administered with phenylbutazone increased plasma war farin concentrations and prothrombin time in normal volun- teers. Phenylbutazone displaces warfarin from its albumin-binding sites in vitro , but this observation cannot be extrapola ted to an in vivo eff ect. Th e observed eff ect is due to changes in drug metabolic cleara nce and not from changes in protein binding. NSAIDs undergo extensive phase I and phase II enzyme biotransformation in the liver, with s ubsequent excretion into urine or bile. Enterohepatic recirculation occurs when a sig- nifi cant amount of an NSAID or its conjugated metabolites are excreted into the bile and then reabsorbed in the distal intestine. Pharmacokinetic parameter estimate variability is large , partly attributable to covariate eff ects of age, size, and pharmacogenom- ics. Ibuprofen , for example, is metabolized by the CYP2C9 and CYP2C8 subfamily. It is known that consider able variation exists in the expression of CYP2C activities among individuals, and function al polymorphism of the gene coding for CYP2C9 has been described. Th e NSAIDs can reduce the antihypertensive eff ect of angi- otensin-converting enzyme inhi bitors and -blockers with possi- ble loss of blood pressure control and can attenuate th e natriuretic eff ect of thiazide diuretics and furosemide. Concurrent administra- tion of probenecid decreases NSAID renal clearance. Lithium and methotrexate concentrations may be increased due to decreased renal clearance. Signifi cant drug interactions have also been d em- onstrated for aspirin, digoxin, cyclosporine, cholestyramine, and colestipol (Davies an d Anderson, 1997 ). NSAID elimination is all too frequently described only in terms of half-life, which is ther efore confounded by volume of distri- bution. Th e plasma half-lives of NSAIDs in adults ra nge from 0.25 to greater than 70 h, indicating wide diff erences in clearance rates. Elimin ation half-lives are longer in neonates than in chil- dren. An elimination half-life of 30. 5 h was reported in premature infants receiving ibuprofen within the fi rst 12 h of life (A randa et al., 1997 ), in contrast with 1.6 h in infants and children aged 3 months to 10 ye ars (Kelley et al., 1992 ). Clearance increases from birth; ibuprofen clearance increases f rom 2.06 ml/h/kg at 22 to 31 weeks postmenstrual age (Aranda et al., 1997 ), 9.49 ml/h/kg a t 28 weeks postmenstrual age (Van Overmeire et al., 2001 ), to 140 ml/h/kg at 5 years (Scot t et al., 1999 ) ( Table 43.4 ). Clearance (L/h/kg) is generally increased in childhood bot h for the established NSAIDs and for the newer COX-2 inhibitors. Th is increased clearance is common for most drugs in childhood. Age-related ketorolac pharmacokinetic parameter esti mates aft er 0.5 mg per kg intravenously are shown in Table 43.5 . Elimination clearance, c orrected for size using an allometric 3 / 4 -power model (Anderson and Holford, 2008 ), is similar to adult estimates from 1 year of age. Data from infants under the age of 1 year su ggest higher clearance estimates of 1.5 ml/min/kg (Cederholm et al., 1992 ; Demiraran et al ., 2008 ). Renal failure Renally excreted NSAIDs such as azapropazone may accumulate in renal failure. Ketoprofen and naproxen are metabolized via the acyl glucuronidation pathway, and also may accumulate in renal failure. Renal impairment is a risk factor for NSAID-induced renal tox icity (Davies and Skjodt, 2000 ). Hepatic disease Hypoalbuminaemia will alter the volume of distribution of NSAIDs. NSAIDs th at are mainly eliminated by hepatic oxidative metabo- lism may require dose reduction, or s hould be avoided in the pres- ence of signifi cant liver disease (Davies and Skjodt, 2000 ) . Safety issues Th e most common adverse events in NSAID recipients are nau- sea, dizziness, and headache. NSAIDs have potential to cause GI irritation, blood clotting disorders, renal impairment, neutrophil dysfunction, and bronchoconstriction; eff ects postulated to be rel ated to COX-1/COX-2 ratios, although this concept may be an oversimplifi cation. COX-2, for example, is constitutively expressed in renal tissues of all species. It seems unlikely th at these COX-2 inhibitors will off er renal safety benefi ts over non-selective NSAID thera pies. It is reasonable to assume that all NSAIDs, including COX-2-selective inhibitors, sha re a similar risk for adverse renal eff ects (Brater et al., 2001 ). Many NSAIDs are formulated as a racemic mixture where only one isomer is active, but where the other may infl uence pharma- cokinetics (stereoselectivity). Ibuprofen stereoselectivit y has been reported in premature neonates (<28 weeks of gestation). R- and S-ibuprofen half -lives were about 10 h and 25.5 h, respectively. Th e mean clearance of R-ibuprofen (12.7 m l/h) was about 2.5- fold higher than for S-ibuprofen (5.0 ml/h) (Gregoire et al., 2004 ). S imilar data have been reported for ketorolac (Hansen et al., 2001 ; Kristensen et al., 1998 ). Single-isomer NSAIDs are appearing for the treatment of acute pain and may have fewer a dverse eff ects than traditional NSAIDs. One other concern is the sudden and profound bradycardia aft er rapid IV administration of ketorolac. Although the mechanism of this response is unclear, ketorolac should be administ ered slowly when given intravenously. Most children are asymptomatic aft er NSAID accidenta l overdose. Symptoms may comprise tinnitus, diarrhea, nausea, blurred vision, drowsiness, v omiting, headache, agitation, confusion, rash, and sweating with increasing dose (e.g. >100 mg/kg ibuprofen). Severe overdose (e.g. ibuprofen >400 mg/ kg) can be life threatening and present with respiratory depression, cardiovascular compromise, metabolic acidosis, renal failure, and altered neurological state. Reports of the use of COX-2 selective inhibitors in children are appearing in the literatur e, but their future use is still uncertain fol- lowing reports of atherothrombosis in adult s. Future benefi ts may be derived from nitric oxide or hydrogen sulfide releasing NSAIDs CHAPTER 43 the non-steroidal anti-inflammatory drugs and acetaminophen 443 Table 43.4 Pharmacokinetic parameter estimates for some commonly used NSAIDs Age No. Formulation CL/F (mL/h/kg) V/F (L/kg) T 1/2 (h) Reference Salicylic acid 0.3 \200\2234 years 6 Suspension ND 0.3 (0.1) 4 (2.1) (Treluyer et al., 1991) 0.8 \200\2231.8 years 5 Suspension ND 0.3 (0.06) 5.6 (6.4) (Treluyer et al., 1991) 5.5 (0.8) years 10 Tablet 22.1 (1.8) 0.113 (0.005) 3.24 (Wilson et al., 1982) Diclofenac 4.3 \200\2236.8 years 10 IV 462 (90) 0.9 (0.25) 1.3 (0.3) (Korpela and Olkkola, 1990) 4 \200\2238 years 26 Suppository 875 0.32 4.2 (van der Marel et al., 2004) 5 \200\22315 years 11 Tablet 754 (207) 0.71 (0.23) 0.65 (0.14) (Romsing et al., 2001) 141 b IV (F = 1), dissolvable tablet F = 0.35, suppository F =0.63 1 \200\22314 years 291 0.21 \200\223 (Standing et al., 2011) Ibuprofen 21 d IV 2.06 (0.33) 0.062 (0.004) 30.5 (Aranda et al., 1997) 22 \200\22331 weeks 13 d 28.6 (1.9) weeks IV 9.49 (6.82) 0.357 (0.121) 43.1 (26.1) (Van Overmeire et al., 2001) 0.5 \200\2231.5 years 11 Suspension 110 (40) 0.20 (0.09) 1.6 (0.4) (Rey et al., 1994) 11 months \200\22311 years 18 Suspension 57.6 0.164 1.97 (Kelley et al., 1992) 3 months \200\22312 years 28 Suspension 80 (SE 10) 0.16 (SE 0.02) 1.44 (SE 0.15) (Brown et al., 1998) 3 months \200\22312 years 39 Suspension 110 (SE 10) 0.22 (SE 0.02) 1.37 (SE 0.09) (Brown et al., 1998) 5.2 (1.7) years 22 Suspension 140 (32) 0.27 (0.11) 1.4 (0.5) (Scott et al., 1999) 5.2 (2.5) years 4 Tablet 114 (26) 0.26 (0.1) 1.6 (0.4) (Scott et al., 1999) 103 b Suspension/ 71 (CV 24%) V c 0.06, V p 0.1 (CV 65%) 0.147 (0.0037) \200\224 (Troconiz et al., 2000) 4 \200\22316 years granules (4.05 L/h/70 kg) 4 \200\22311 years 24 suspension 77.5 (16.4) 1.3 (Granfors et al., 2004) Indomethacin 28.8 (2.5) weeks c 83 e IV 2.63 \227 wt (kg) + 0.244PNA (d) mL/h (CV 77%) 0.28 \227 wt (kg) + 0.0041PNA (d) L (CV 28%) (Wiest et al., 1991) 5.7 (4.7) days d 1.2 \200\2234.6 years 14 IV 192 (102) 0.74 (0.75) 6.1 (4.9) (Olkkola et al., 1989) Ketoprofen 7 months \200\22316 years 18 IV 90 (60 \200\223130) 0.16 (0.12 \200\2230.21) 1.3 (0.8 \200\2231.7) (Kokki et al., 2002) Ketorolac 0.4 \200\22333 weeks 12 IV 100 0. 18 _ (Cederholm et al., 1992) 2 \200\22311 months 17 IV 89.4 (69.2) 0.31 (0.11) 3.9 (2.8) (Demiraran et al., 2008) 1 \200\22316 years 36 IV 34.2 (10.2) 0.113 (0.033) \200\223 (Dsida et al., 2002) 4 \200\2238 years 10 IV 42 (30 \200\22358) 0.26 (0.19 \200\2230.44) 6.1 (3.5 \200\22310) (Olkkola and Maunuksela, 1991a) 3 \200\22318 years 50 IV 66 (30) 0.35 (0.2) 4.1 (2.3) (Kau \200 man et al., 1999) 3.3 \200\2238 years 7 IV 80 (50) 0.26 (0.17) 2.26 (1.35) (Gonzalez-Martin et al., 1997) 2.6 \200\2237.3 years 7 IV 70 (30) 0.21 (0.08) 2.09 (0.57) (Gonzalez-Martin et al., 1997) (Continued) SECTION 6 pharmacological interventions 444 Table 43.4 (Continued) Age No. Formulation CL/F (mL/h/kg) V/F (L/kg) T 1/2 (h) Reference Naproxen 8.1 \200\22314.1 years 12 Tablet 9.2 (2.6) 0.11 (0.02) 8.1 (2.1) (Wells et al., 1994) 10.4 \200\22314.1 years 10 Suspension 9 (2.4) 0.13 (0.03) 9.6 (3.2) (Wells et al., 1994) a Variability is given in parentheses as SD, range, or SE. CL / F = apparent drug plasma cl earance; IV = intravenous; T 1/2 = elimination half-life; V / F = apparent volume of distri bution; V c = initial volume of distribution; V p = apparent volume of distribution of peri pheral compartment, ND = not determined, CV = coe \203 cient of variation; PNA = postnatal age. b Data reported using allometric model. Estimate presented for a 30 kg individual. c Age is gestational age (weeks). d Covariates age and weight included in parameter estimates . Adapted from Seminars in Fetal and Neonatal Medicine , Volume 11, Issue 4, Jacqz-Aigrain E and Anderson BJ, Pain Control \200\224Nonsteroidal anti-in \202 ammatory agents, pp. 251 \200\223259, Copyright 2006, with permission from Elsevier, http://www.sciencedirect.com /science/journal/1744165X. Table 43.5 Ketorolac age-related pharmacokinetic changes Age (years) Weight (kg) V ss (SD) (L/kg) CL (SD) (mL/min/kg) CL std (SD) (mL/min/70 kg) 1 \200\2233 12 0.111 (0.025) 0.6 (0.2) 27.0 (9.0) 4 \200\2237 20 0.128 (0.047) 0.61 (0.22) 31.2 (11.3) 8 \200\22312 30 0.099 (0.014) 0.54 (0.15) 30.6 (8.5) 12 \200\22316 50 0.116 (0.040) 0.51 (0.12) 32.8 (7.7) Adult (Mandema and Stanski, 1996) 70 0.18 0.47 32.7 V ss = volume of distribution at steady state; CL std = total body clearance standardized t o a 70 kg person using an allometric 3 / 4 -power model; weight is estimated. Data are from Dsida et al. ( 2002 ). Reprinted with permission from Caroline D. van der Marel et al., Diclofenac and metabolite pharmacokinetics in children, Pediatric Anesthesia , Volume 14, Issue 6, pp. 443 \200\22345 1, Copyright 2004 Blackwell Publishing Ltd, http://onlinelibrary.wiley.com/journal/10.11 11/%28ISSN%291460-9592. Renal e \200 ects Th e eff ect of short-term treatment with NSAIDs on healthy kid- neys is negligible. Ibuprofen reduced the glomerular fi ltration rate by 20% in premature neonates , aff ecting aminoglycoside clearance, and this eff ect appears independent of gestational age (Allegaert et al., 2005 ). Large studies involving ibuprofen (Lesko and Mitchell, 1997 , 1999 ) and ketorolac (Houck et al., 1996 ) have shown little risk in children (e.g. upper 95% bound was 5.4 per 100 000 ibuprofen- treated children). Similar data are reported in c hildren suff ering juvenile rheumatoid arthritis (JIA) given NSAIDs as long-term treatment. However, renal compromise is described in children suff ering dehydration, hypovolaemia, h ypotension, or pre-existing renal disease. NSAIDs may also potentiate the toxicity of other drugs such as aminoglycosides and ciclosporin. Bone healing NSAIDs, but not acetaminophen, impair fracture healing in animal models. COX-2 activity plays an important role in bone healing and the use of NSAIDs decreases osteogeni c activity that may increase the incidence of non-union aft er spinal surgery. Th e eff ect on osteo- genic activity is dose-dependent and reversible. Th ese eff ects are cause for c oncern aft er major orthopedic surgery (Dodwell et al., 2010 ), but there was no risk of no n-union with NSAID exposure when high-quality studies were assessed. Bleeding propensity Th e commonly used NSAIDs such as ketorolac, diclofenac, ibupro- fen, a nd ketoprofen have reversible antiplatelet eff ects, which are attributable to the inhibiti on of thromboxane synthesis. Bleeding time is usually slightly increased in the perioperati ve period, but it remains within normal limits in children with normal coagula- tion system s. A Cochrane review has established that even aft er tonsillectomy, NSAIDs did not cause a ny increase in bleeding that required a return to theater in children (Cardwell et al., 200 5 ). Th ere was signifi cantly less nausea and vomiting with NSAIDs compared to alternative analgesics, suggesting their benefi ts outweigh their negative aspects. Gastrointestinal e \200 ects Adverse GI eff ects are signifi cant in adults, particularly in those with peptic ulcer disease, Helicobacter pylori , or advanced age. Th e risk of acu te GI bleeding in children given short-term ibuprofen was estimated to be 7.2 in 100 000 (9 5% CI, 2 \200\22318 in 100 000) (Lesko and Mitchell, 1995 , 1999 ) and was not diff erent f rom those chil- dren given acetaminophen. Similar data are reported in children given ketor olac for acute pain (Forrest et al., 1997 ). Th e incidence of clinically signifi cant gast ropathy is comparable to adults in chil- dren given NSAIDs for JIA (Dowd et al., 1995 ; Kee nan et al., 1995 ), but gastroduodenal injury may be very much higher depending on assessme nt criteria. Th e use of ketorolac analgesia for tonsillectomy, however, has been associated with increa sed bleeding. Th is was attributable to the dose used and whether it is given preoperativel y or postoperatively and duration of therapy (Strom et al., 1996 ). Th e risk associated wi th the drug was larger and clinically important when ketorolac was used in CHAPTER 43 the non-steroidal anti-inflammatory drugs and acetaminophen 445 higher doses, in older subjects, and for more than 5 days. It is reason- able to not admini ster this medication until the end of surgery aft er haemostasis is achieved. Forrest et al . have suggested an IV dose of ketorolac in children of 0.5 mg/kg, followed either by bolus injections of 1.0 mg/kg every 6 h or an IV infusion of 0.17 mg/kg/h (Forrest et al., 1997 ). Th e maximum daily dose is 90 mg, and the maximum duration of treatment is 48 h. Th e re commended oral dosage is 0.25 mg/kg to a maximum of 1.0 mg/kg/day, with a maximum duration of 7 days. Disparities between results may stem from diff erences in the endpoint studied (particularl y for assessments of analgesia) and dissimilar dosing regimens, as well as a plethora of ot her factors relating to study design, conduct and analysis. Dose \200\223response curves pu blished in adults (Mehlisch et al., 2010 ) for combination acetaminophen-ibuprofen therapy have been investigated for com- bination therapy response. Pain aft er dental surgery was m easured using pain intensity diff erences (PRID, 0 \200\2238) from 0 to 8 h. Analysis of th e response surface area ( Figure 43.9 ) allowed dose interpre- tation in children (Hannam a nd Anderson, 2011 ). Simulation for a 20 kg child showed the addition of acetaminophen to i bupro- fen doses of less than 5 mg/kg was eff ective; acetaminophen had minimal eff ect whe n given with ibuprofen at doses greater than 5 mg/kg in the immediate postoperative period. A more sustained analgesic eff ect was noted at 4 to 8 h aft er combination dosing ( Figur e 43.10 ). Asthma Aspirin or NSAID exacerbated respiratory disease (ERD) is more a disorder of adults but exacerbations in children and teenagers have been reported. Th is adverse eff ect is co untered by a benefi cial reduction of asthma symptoms where ibuprofen was administered for antipyresis. Benefi t is likely seen in younger children with mild episodic asthma and ERD is a concern in one in three teenagers with severe asthma and coexistent nasal disease. COX -2 inhibitors are reported as safe in NSAID-ERD (Palmer, 2005 ). Hepatotoxicity attributed to the therapeutic administration of acetaminophen Th e acetaminophen \200\223NSAID interaction Acetaminophen and NSAIDs are oft en given toge ther for the man- agement of pain or fever. Th ey can be safely combined without increases in their associated adverse eff ect profi les and combina- tion therapy is popular. A revie w of randomized controlled studies comparing combined acetaminophen and ibuprofen therapy f or postoperative pain management identifi ed six studies (Ong et al., 2010 ). Of these, thr ee were conducted in pediatric populations: oral premedication with acetaminophen and ibupr ofen was sup- ported over acetaminophen alone for tonsillectomy pain in children and follow ing tooth extraction; while rectally administered aceta- minophen and ibuprofen showed no b enefi t over acetaminophen alone for pain following adenoidectomy, although a reduction in rescue analgesia was seen in the combination group once home. Case example A 3-year-old boy suff ered a depressed compound right-sided skull fracture with underlying brain contusion. He presented 1 h aft er injury with apnoea, hypovolaemia, and a Glasgow Co ma Score of 6/15. Intubation, ventilation, volume resuscitation, and inotropes were institu ted and the child went forward for emer- gency right fronto-temporal craniotomy and debride ment of the fracture site. Postoperatively he remained stable. Prophylactic phenytoin was u sed for possible seizure activity and intermittent phenobarbital for sedation. Acetaminophe n 100 mg/kg/day was administered through the nasogastric tube to control hyperpy- rexia. Se rum concentrations of acetaminophen were not meas- ured. Serum aspartate aminotransferase ( AST) was elevated to 610 IU/L on day 2. On day 3 he developed a metabolic acidosis with a b ase defi cit of 9 mmol/L. Th ere was a dramatic rise in AST (10 000 IU/L) and a moderate in crease in gammaglutamyltrans- ferase (GGT 113 IU/L) concentrations. Th e coagulation profi le was disordered (APTT 79, PR 3.3, fi brinogen 1.6g/L). 4 3 e r o c S D R P 2 Abdominal contrast-enhanced computed tomography (CT) revealed a large wedged-shaped area of non-enhancement in the right lobe of the liver with a large volume of free intraperitoneal fl uid in the hepatorenal fossa, the right paracolic gutter, and the lesser sac of the pel vis. Th e lesion was assumed to represent a lac- eration and was managed conservatively; ho wever, over the sub- sequent 48 h the child developed fulminant hepatic failure with multip le system organ involvement. Treatment was withdrawn on day 5. I 1 0 24 24 20 20 16 16 12 12 8 8 4 4 0 Aoeterminophen concentration (mg.L \200\2231) Ibuprofen concentration (mg.L \200\2231) Figure 43.9 Th eoretical response surface of e \200 ect between acetaminophen and ibuprofe n. Concentrations are those in the e \200 ect compartment. Th e concentration response for acetaminophen is plotted on the x \200\223y axis, while that for ibuprofen is on the z \200\223y axis. Th e \200\230surface \200\231 is that plotted between these axes. Reproduc ed with permission from Jacqueline Hannam and Brian J. Anderson, Explaining the acetaminoph en \200\223ibuprofen analgesic interaction using a response surface model, Pediatric Anesth esia , Volume 21, Issue 12, pp. 1234 \200\2231240, Copyright 2011 Blackwell Publishing L td, http://onlinelibrary.wiley.com/ journal/10.1111/%28ISSN%291460-9592. Postmortem liver sections showed coagulative necrosis involv- ing zone 3 which, in some are as, extended into zone 2 of the liver acinus. Th ere was sparing of periportal areas. Th e portal triads were unremarkable. Th ere was a mild acute infl ammatory response associated with the coagulative necrosis. Th ere was no evidence of centrilobular congestion or sinuso idal engorgement. Th ere was no evidence of a laceration in the right lobe. SECTION 6 pharmacological interventions 446 5 4 3 e r o c S D I R P 2 1 0 0 1 2 3 4 5 6 7 8 9 Time (hours) 200mg acetaminophen 400mg acetaminophen 25mg ibuprofen 100mg ibuprofen 200mg ibuprofen 300mg acetaminophen + 25mg ibuprofen 300mg acetaminophen + 50mg ibuprofen 400mg acetaminophen + 50mg ibuprofen 400mg acetaminophen + 200mg ibuprofen Figure 43.10 Simulated PRID scores for a 5-year-old, 20 kg child given single and combinati on acetaminophen-ibuprofen therapy. Reproduced with permission from Jacqueline Hannam and B rian J. Anderson, Explaining the acetaminophen \200\223ibuprofen analgesic interaction usin g a response surface model, Pediatric Anesthesia , Volume 21, Issue 12, pp. 1234 \200\22312 40, Copyright 2011 Blackwell Publishing Ltd, http://onlinelibrary.wiley.com/journal/10.1 111/%28ISSN%291460-9592. Discussion In the case example, acetaminophen was implicated as a cause of hepatic necrosis in the child. Diagnosis was delayed because CT abdominal fi ndings, performed 3 days aft e r the presenting injury, were misinterpreted as hepatic trauma. Th e pattern of necrosis de scribed in this child \200\231s liver is consistent with damage related to acetaminophen wh ere zone 3 is the main area of concentration of the enzyme system responsible for the conve rsion of acetami- nophen into hepatotoxic metabolites. None of the other drugs used in his management are commonly implicated in hepatoxicity, although co-administration of anticonvu lsants may induce hepatic microsomal enzymes resulting in increased NAPQI aft er subse- que nt acetaminophen administration. While some anticonvulsant drugs may induce CYP2E1, phenyto in and phenobarbital are not metabolized through CYP2E1 and have not been considered to be CYP2E1 inducers, although there are reports that suggest pheno- barbital induces a modest i ncrease (1.7-fold) in CYP2E1 (Madan et al., 2003 ). hepatic transaminase concentrations with peak concentrations occurring within 24 h of the i schaemic episode. It is likely that the combination of therapeutic acetaminophen doses in t he presence of a liver compromised by ischaemic hepatitis, contributed to this boy \200\231 s death. Consideration should be given to both the indication for acetaminophen and the dose in chil dren with hepatic pathol- ogy. Acetaminophen has poor eff ect on temperature changes due to cerebral pathology. Temperature reduction in this child would have been better achieved by external cooling and neuromuscu- lar blockade to prevent shivering. Acetaminophen contribu tes lit- tle additional analgesia and does not reduce opioid adverse eff ects when used to supplement morphine (Maund et al., 2011 ). Th e use of acetaminophen to control fever conti nues to be debated. It has not been established conclusively that the benefi ts of antipyre tic therapy outweigh its risks (Plaisance and Mackowiak, 2000 ). References Allegaert , K. , Cossey , V. , Debeer , A. , Langhendries , J. P. , Van Overmeir e , B. , De Hoon , J. , et al . ( 2005 ). Th e impact of ibuprofen on renal clearance in pr eterm infants is independent of the gestational age . Pediatr Nephrol , 20 , 740 \200\2237 43. Acetaminophen has recognized hepatotoxicity aft er doses above 150 mg/kg in children (Penna and Buchanan, 1991 ), although data subsequent to this report has implicated lower thresho ld doses (75 \200\22390 mg/kg/day) used for 3 days or more (Kearns et al., 1998 ). Children may have raised serum concentrations aft er 2 \200\2233 days of repeated therapeutic doses , resulting in hepatic damage. Liver func- tion is further reduced in the presence of ischa emic hepatitis, which occurs in association with severe shock and is due to a reduction in liver blood fl ow. Th e condition is manifested by elevation of plasma Allegaert , K. , Murat , I. , and Anderson , B. J. ( 2007 ). Not all intravenous paracetamo l formulations are created equal . Paediatr Anaesth , 17 , 811 \200\223812. Allegaert , K. , Palmer , G. M. , and Anderson , B. J. ( 2011 ). Th e pharmacokinetics of i ntravenous paracetamol in neonates: size matters most . Arch Dis Child , 96 , 575 \200\223 580. CHAPTER 43 the non-steroidal anti-inflammatory drugs and acetaminophen 447 Demiraran , Y. , Ozturk , O. , Guclu , E. , Iskender , A. , Ergin , M. H. , and Tokmak , A. ( 2008 ). Vasoconstriction and analgesic effi cacy of locally infi ltrated levobupivacaine for nasal surgery . 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