Effects of Perioperative Antiinflammatory and Immunomodulating Therapy on Surgical Wound Healing

Anthony J. Busti, PharmD; Justin S. Hooper, PharmD; Christopher J. Amaya, PharmD; Salahuddin Kazi, MBBS

Pharmacotherapy. 2005;25(11):1566-1591.

Conclusion

All patients with autoimmune diseases requiring immunomodulating therapy who are undergoing surgery should be monitored carefully for the development of infection as well as disease flare-ups. Data are limited, and in some cases inconsistent, regarding the use of immunomodulating therapy in the perioperative period. In some cases, our decision-making relies on the extrapolation of results from animal studies to clinical practice. Health care providers should consider the patient's comorbidities, risk factors for postoperative complications, and the pharmacokinetics and pharmacodynamics of corticosteroids, NSAIDs, COX-2-selective inhibitors, DMARDs, and biologic response modifiers when making final decisions regarding these agents' perioperative use. More prospective, controlled studies are needed to define the effects of these agents on the process of bone and wound healing in the surgical setting.

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Acknowledgments

We thank Bryan Poon, Pharm.D., for his input into this paper.

Reprint Address

Address reprint requests to Anthony J. Busti, Pharm.D., BCPS, Department of Pharmacy Practice, Texas Tech University Health Sciences Center, School of Pharmacy at the Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Dallas, TX 75216; e-mail: anthony.busti@ttuhsc.edu .

References

Studies Evaluating Cyclooxygenase-2 Inhibitors and Nonsteroidal Antiinflammatory Drugs in the Perioperative Setting
Study Design	No. of Subjects	Treatment	Results
In vivo, rats^[31]	53	Aspirin vs controls	Rats given 75 and 150 mg/kg before and after incision had a 22% inhibition of tensile strength. A dose of 150 mg/kg the day before surgery led to a 40% inhibition. Aspirin retards wound healing.
In vitro, rat tissue^[32]	20	Ketorolac vs placebo	A significant decrease in mean breaking strength and mean collagen concentration was noted in ketorolac-treated rats.
Rabbit tissue^[33]	68	Indomethacin vs placebo	After 4 wks, in the indomethacin-treated group, a significant decrease in 4-hydroxyproline and proline content in tendons was found, indicating a decrease in collagen synthesis.
In vitro, rat skin^[34]	10	Ibuprofen vs diclofenac vs placebo	16-36% reduction in wound strength was noted in treatment groups as measured by tensile strength.
Rat tissue^[35]	45	Ibuprofen vs placebo	Ibuprofen was found to decrease neutrophil activity, lymphocyte blastogenesis, and helper or inducer T-lymphocyte infiltration on a sponge model matrix.
In vitro, human tendon^[36]	10	Diclofenac vs aceclofenac vs indomethacin vs naproxen	Diclofenac and aceclofenac had no significant effect, but indomethacin and naproxen significantly reduced tendon cell proliferation and glycosaminoglycan synthesis in patellar tendon cultures.
Retro, human^[37]	165	NSAIDs^a vs no NSAIDs	Patients taking more NSAIDs had more postoperative bleeding complications than did patients not taking NSAIDs. Complications were more frequent with NSAIDs with a half-life > 6 hrs.
MC, P, R, DB^[38]	175	Parecoxib	Postoperative administration of parecoxib 20 and 40 mg i.v. significantly reduced PCA morphine use over a 24- and 36-hr period with no difference in adverse events.
P, R, MC, PC, DB, PG, human^[39]	418	Celecoxib vs hydrocodone-APAP vs placebo	Single doses of each were administered within 24 hrs after anesthesia. Over 8 hrs, celecoxib and hydrocodone-APAP offered equal analgesia. Over a 5-day period, celecoxib 200 mg t.i.d. was superior in analgesia and tolerability than hydrocodone-APAP 10 mg-1000 mg t.i.d. This study was not designed to evaluate wound healing or adverse effects.
P, rats^[40]	~75	Diclofenac vs naproxen vs nabumetone vs etodolac vs L745,337	Administration of the potent COX-2 inhibitor, L745,337, to rats with induced colitis led to excessive mortality compared with other NSAIDs.
P, mice^[41]	NR	NS-398 vs control	NS-398, a selective COX-2 antagonist, impairs healing of induced gastric ulceration in mice.
P, R, in vivo, mice^[42]	NR	Diclofenac vs SC-791 (COX-2 inhibitor) vs dexamethasone (used as control)	Diclofenac did not have any significant effect on the wound healing morphology. Tensile strength was not affected by the use of diclofenac or dexamethasone
In vitro, rats^[43]	5	Celecoxib vs naproxen vs HCT-3012	Celecoxib did not significantly affect collagen deposition into subcutaneously implanted sponges.
P, R, PC, DB, human knee^[44]	21	Rofecoxib vs placebo	Though not designed to evaluate wound healing issues, no adverse effects or complications were reported after total knee replacement. Rofecoxib was started 3 days before and continued for 48 hrs after surgery.
In vivo, rat femur^[45]	129	Indomethacin vs placebo	Indomethacin group had significantly more angulation at 24 days, and significantly decreased tensile strength, indicating poor fracture repair compared with placebo group.
In vivo, rabbit tibia^[46]	32	Indomethacin vs placebo	Formative foci were reduced at 2 and 6 wks after tibial osteotomy, indicating inhibition of bone formation.
In vivo, rabbit ulnae^[47]	27	Ketorolac 2 mg/kg vs methylprednisolone vs ketorolac 4 mg/kg vs control	Demineralized bone implanted into rabbits had lower torsional stiffness in treatment groups compared with controls and higher doses of ketorolac. Methylprednisolone led to decreased number of well-differentiated osteocytes.
In vivo, rat tibia^[48]	59	Ibuprofen vs placebo	Treatment groups had significantly lower calcium levels. Rats in the fracture group also had lower hydroxyproline levels compared with rats in the placebo group.
In vivo, rabbit L5-L6 arthrodesis^[49]	70	Indomethacin vs control	Starting indomethacin 2 and 4 wks postoperatively led to lower fusion rates compared with controls.
Retro, PC, PG, human^[50]	288	Ketorolac vs control	Patients who received ketorolac postoperatively had significantly higher nonunion rates compared with patients who received no NSAIDs.
P, R, in vivo, rat femur^[51]	253	Indomethacin vs celecoxib vs rofecoxib vs placebo	COX-2 inhibitor groups still had fracture evidence at wk 8 vs normal healing in controls. Rofecoxib led to a significantly reduced torque and torsional rigidity at 4 and 8 wks after fracture. Indomethacin and rofecoxib groups had significantly reduced normalized shear stress at 4 and 6 wks after fracture, which remained significantly lower at 8 weeks in the rofecoxib group.
In vitro, rats^[52]	50	Celecoxib vs no treatment	Celecoxib-treated and injured rats were determined to have a 32% lower load to failure than untreated and noninjured rat ligaments, but the long-term effect on healing is not known.
P, R, in vivo, rat femur^[53]	8	Etodolac vs placebo	Etodolac delayed femur fracture union and callus formation in rats 3 wks after fracture. Strength and stiffness were significantly lower in the etodolac treatment group than in the placebo group.
In vivo, rat femur^[54]	48	Ketorolac vs parecoxib	3 wks after femur fracture, 25% of the ketorolac group fractures and 8% of the high-dose parecoxib group fractures failed to unite.
In vivo, rat femur^[55]	57	Indomethacin vs celecoxib vs control	At 4 and 8 wks after fracture, both selective and nonselective COX-inhibited treatment groups had significantly more fibrous tissue and less woven bone formation vs nontreatment group.

Retro = retrospective; NSAIDs = nonsteroidal antiinflammatory drugs; MC = multicenter; P = prospective; R = randomized; DB = double blind; PC = placebo controlled; PG = parallel group; PCA = patient-controlled analgesia; APAP = acetaminophen; COX-2 = cyclooxygenase-2; NR = not reported.
^aNSAIDs were indomethacin, sulindac, tolmetin, ibuprofen, ketoprofen, naproxen, fenoprofen, meclofenamate, aspirin, and piroxicam.

Studies Evaluating Disease-Modifying Antirheumatic Drugs in the Perioperative Setting
Study Design	No. of Subjects	Treatment	Results
Retro, human^[81]	80	Methotrexate vs prednisolone vs combination	No overall statistically significant risk of wound infection or breakdown after hand surgery in all groups. No flare-ups occurred in 3 mo after surgery, except in those with diabetes (33% vs 3.3%).
Retro, human^[82]	66	Methotrexate stopped immediately before surgery	Methotrexate was not associated with increased risk of wound complications after orthopedic surgery; however, 8 complications (of the 66 procedures) occurred, with 3 being major complications.
	32	Azathioprine	The preoperative use of azathioprine was associated with a doubling of the risk of complications (RR 2.13, 95% CI 1.04-4.37).
Retro, human^[83]	121	Methotrexate vs controls	8 patients with rheumatoid arthritis taking methotrexate (mean 8.2 mg) had 8 complications compared with 5 patients not taking methotrexate who had 6 complications (p=0.366) after total joint arthroplasty.
Retro, human^[84]	15	Methotrexate vs controls	No difference in postoperative infection or wound healing among patients with rheumatoid arthritis undergoing reconstructive surgery of the hand and wrist.
P, R, C, human^[85]	388	Methotrexate continued vs methotrexate stopped vs controls	Infections or surgical complications after orthopedic surgeries occurred in 2% of patients who continued methotrexate, 15% in those who stopped methotrexate 2 wks before until 2 wks after procedure, and 10.5% in controls. Rate of complications was less in patients who continued methotrexate vs those who stopped methotrexate (p<0.003).
P, R, human^[86]	64	Methotrexate stopped for 7 days vs no interruption in therapy	No difference in postoperative orthopedic complications between 32 patients who stopped methotrexate before surgery and 32 who did not stop methotrexate.
Retro, human^[87]	38	Methotrexate stopped ≥ 4 wks vs methotrexate stopped < 4 wks	More postoperative complications (joint infection, wound dehiscence) in patients with rheumatoid arthritis undergoing elective orthopedic surgery who continued methotrexate until < 4 wks before surgery vs those who stopped methotrexate Ž 4 wks (p<0.03).
P, human^[88]	32	Methotrexate stopped vs methotrexate continued	Those stopping methotrexate had no postoperative (total joint arthroplasty or fusion) infections, whereas those not stopping methotrexate had 4 postoperative infections. Temporary discontinuation of methotrexate 1 wk before surgery seemed to decrease postoperative infections.
O, human^[89]	48	D-penicillamine, gold, azathioprine, resochin	The agents did not influence the rate of healing or increase the frequency of operative reintervention. No interruption in treatment was suggested.
P, human^[90]	21	D-penicillamine with or without prednisolone	No difference in mean healing times for patients with rheumatoid arthritis undergoing orthopedic surgery who received D-penicillamine alone (19.8 ± 13.1 days) vs those taking D-penicillamine + corticosteroids (19.3 ± 10.1 days).
P, rats^[91]	~40	Azathioprine vs prednisolone vs combination vs control	Abdominal wall breaking strength was greatest in azathioprine-treated group. The combination regimen did not significantly alter wound healing.

Retro = retrospective; RR = relative risk; CI = confidence interval; P = placebo; R = randomized; O = observational, C = controlled.

Studies Evaluating Biologic Response Modifiers in the Perioperative Setting
Study Design	No. of Subjects	Treatment	Results
Retro, human^[100]	270	Steroids ± immunosuppressives (azathioprine, 6-mercaptopurine, methotrexate) ± infliximab	Patients with Crohn's disease who were taking these drugs underwent abdominal surgery and were evaluated for prevalence of septic and nonseptic complications within 30 days of surgery. No association was noted between the use of infliximab, steroids, or immunosuppressives and postoperative complications.
Retro, human^[101]	100	Azathioprine, methotrexate, 6-mercaptopurine, or infliximab vs no therapy	Immunomodulator use in patients with Crohn's disease undergoing bowel reanastomosis or strictureplasty was associated with fewer septic complications compared with patients not taking therapy (5.6% vs 25%, p=0.01, OR 5.68, 95% CI 1.51-21.3).
P, human^[102]	31	Etanercept or infliximab vs no TNF-α inhibitor therapy	Etanercept- and infliximab-treated patients were significantly similar to patients not receiving TNF-a inhibitors regarding healing and infectious complications after elective foot and ankle surgery.
Retro, human^[103]	29	Infliximab	86% of patients with Crohn's disease treated with infliximab for perianal fistulas had a complete or partial response; 14% had no response, but the number of adverse events was low. No surgical intervention was performed during the study.

Retro = retrospective; OR = odds ratio; CI = confidence interval; P = prospective; TNF = tumor necrosis factor.

Studies Evaluating Corticosteroids in the Perioperative Setting
Study Design	No. of Subjects	Treatment	Results
P, rat^[126]	37	Cortisone vs no treatment	After wounding and long-term cortisone (5 mg/kg/day), rats were sacrificed and tissue samples were taken from sites of wounding. Tissue was loaded to breakage with a materials-testing machine. Cortisol-treated rats had skin wounds that demonstrated decreased failure energy compared with tissue taken from controls.
P, rabbits^[127]	18	Prednisone vs placebo	Rabbits were given prednisone 0.15 mg/kg/day for 2 mo, then underwent osteotomy of the forelimb ulna. After 6 wks, rabbits were sacrificed and radiographs were examined to determine osteotomy healing: 81% of control forelimbs exhibited bone union; only 15% of prednisone-treated limbs were united. Controls also showed significantly greater bone mineral density and content.
P, rabbits^[128]	20	Cortisone acetate vs methylprednisolone vs medroxy- progesterone vs methylprednisolone + medroxy- progesterone vs control	Rabbits were wounded and given one of these regimens. Wound contracture and epithelialization were measured in each group. Wound epithelialization was delayed in rabbits receiving cortisone acetate compared with controls (25 vs 20.5 days).
P, rabbits^[129]	72	Prednisone vs control	Thoracic aorta (in situ) was damaged, and animals were administered prednisone 2 mg/kg/day i.m. for 2 wks. Corticosteroid administration suppressed collagen synthesis and intimal growth.
P, rats^[130]	40	Prednisolone vs vitamin A vs combination vs control	Silicon-sponge discs were implanted under the skin of rats receiving one of the regimens listed. Animals receiving a corticosteroid had a decrease in inflammatory cell infiltration and collagen deposition on the sponge implants.
Retro, O, human^[131]	38	Abdominal surgery patients receiving corticosteroids	Patients undergoing surgery were divided into groups according to length of preoperative corticosteroid use: 28% of patients in the long- term (> 7 days) group had wound healing complications, and 33% of patients in the short-term group had complications.
Retro, human^[132]	111	Prednisolone	Patients with rheumatoid arthritis taking corticosteroids who underwent orthopedic surgery were compared with patients without rheumatoid arthritis taking no steroids. No abnormalities in wound healing were found except in those taking steroids for > 3 yrs.
Retro, human^[133]	26	Compression arthrodesis vs internal fixation ± prednisone	4 of 7 patients who failed arthrodesis were taking prednisone 17 mg/day (mean) preoperatively. Of 19 successful procedures, 11 patients took prednisone 6 mg/day (mean). These data suggest higher failure rates of compression arthrodesis with concomitant use of higher dosages of prednisone.

P = prospective; Retro = retrospective; O = observational.

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