Incidence, severity and reversibility of acute kidney injury after elective hip and knee arthroplasty in patients receiving celecoxib perioperatively as one of the standard multimodal analgesic protocols

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Incidence, severity and reversibility of acute kidney injury after elective hip and knee arthroplasty in patients receiving celecoxib perioperatively as one of the standard multimodal analgesic protocols

https://doi.org/10.21203/rs.3.rs-2497497/v1

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Background Acute kidney injury (AKI) may complicate up to 10% of primary lower-extremity total joint arthroplasties. However, none of these previous studies evaluated the duration and reversibility of AKI. Moreover, none specifically evaluated the impact of perioperative celecoxib on the incidence and severity of AKI, especially for patients with preexisting renal impairment.

The aim of this study was to retrospectively review the incidence, severity and duration of AKI with short term perioperative celecoxib. We also aimed to evaluate the impact of perioperative celecoxib on the incidence and severity of AKI in patients with and without preexisting renal impairment.

Methods We retrospectively reviewed 1077 patients at Queen Mary Hospital, Hong Kong, from January 2018 to December 2021. Data were retrieved from the computerized medical records system.

Results One hundred of 1077 patients (9.3%) had postoperative AKI. Eight hundred eighty-eight patients (82.5%) were prescribed perioperative celecoxib, while 189 patients (17.5%) were not.

The overall incidence of AKI in those taking perioperative celecoxib was 9.2%, while it was 9.5% in those not taking perioperative celecoxib. There was no statistically significant difference. There was no association between perioperative celecoxib and postoperative AKI.

Among those who received perioperative celecoxib, the overall incidence of postoperative AKI in those with and without preexisting renal impairment was 9.3% and 9.2%, respectively. This was not statistically significant. The duration of AKI was 4 days for both groups. In both groups, most AKI cases were stage 1.

Conclusions Short term perioperative celecoxib probably had no additional AKI risk even in patients with preexisting renal impairment. Trial Registration ClinicalTrials.gov registration number NCT05595694.

Trial Registration

ClinicalTrials.gov registration number NCT05595694

Acute kidney injury

perioperative celecoxib

renal impairment

Osteoarthritis (OA) is the most common joint disease, affecting more than 240 million people worldwide, with more than 32 million in the US. Osteoarthritis is the most frequent cause of limited activity in adults [1]. Hip and knee arthroplasty are common orthopedic procedures used to treat patients with end-stage knee arthritis. The demands for these procedures are increasing with time. Hip and knee arthroplasty is a rehabilitative surgery aimed at accelerating patient ambulation and reducing the length of hospital stay. To facilitate this process, multidisciplinary enhanced recovery after surgery (ERAS) programs are implemented [2]. This involves surgeons, anesthetists, physiotherapists and nurses who follow an integrated care pathway to facilitate early patient mobilization, thus leading to early hospital discharge. The program is implemented to reduce the hospital length of stay, which can reduce the risks of complications and mortality [3, 4]. Hip and knee arthroplasty is associated with significant perioperative pain, which can adversely affect recovery by increasing the risk of complications, length of stay, and cost [5]. Severe perioperative pain is associated with an increased risk of infection, myocardial ischemia, respiratory complications and the development of chronic pain [6]. Therefore, effective multimodal analgesia is an essential component in the ERAS program. It combines different oral analgesics to limit opioid use and its related side effects. Cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib, have been shown to relieve pain and reduce opioid use after hip and knee arthroplasty. It is therefore recommended to be used routinely [7, 8]. However, its potential nephrotoxic property has led to its judicious use, especially in patients with preoperative chronic renal impairment.

Postoperative acute kidney injury (AKI) is an independent risk factor for mortality, cardiovascular complications, health care utilization and hospitalization [9–12]. Acute postoperative kidney injury was significantly correlated with increased length of hospital stay [10]. Acute kidney injury may complicate up to 10% of primary lower-extremity total joint arthroplasties and up to 25% of periprosthetic joint infections treated with a 2-stage procedure, including placement of an antibiotic-loaded cement spacer in the first stage [10, 13–22]. None of the above studies showed the reversibility of AKI in the immediate postoperative period following hip and knee arthroplasty. Moreover, none of the above studies showed a specific evaluation of the impact of perioperative celecoxib as part of routine standard multimodal analgesic protocols on the incidence and severity of AKI, especially for patients with preexisting renal impairment.

Therefore, the aim of this study was to retrospectively review the incidence, severity and duration as well as the possible reversibility of AKI following elective hip and knee arthroplasty with perioperative celecoxib as part of the standard multimodal analgesic protocols. We also aimed to specifically evaluate the impact of perioperative celecoxib on the incidence and severity of AKI in patients with and without preexisting renal impairment.

This retrospective review was approved by the local research ethics committee and the requirement for informed consent was waived (UW22-230). We performed a retrospective review of 1077 patients in our database who underwent elective hip and knee arthroplasty at Queen Mary Hospital, Hong Kong, from January 2018 to December 2021. Relevant data were retrieved from the computerized medical records system. Patients who were scheduled to undergo hip and knee arthroplasty were routinely assessed by anesthetists in a preoperative assessment clinic. They were enrolled in an ERAS program, and a multimodal analgesic protocol was started. Oral analgesics were prescribed, including paracetamol 1 g three times per day for 1 week, pregabalin 50 mg or 75 mg at night for 1 week, depending on body weight, and oxycodone sustained release 5 mg twice per day for 2 days. If the patient’s preoperative renal serum creatinine was < 200 µmol/L, 200 mg celecoxib was administered at night immediately before operation day and for 5 days postoperatively. The final decision for prescribing celecoxib was made by the attending anesthetist. Local infiltration of anesthetics (LIA) using 300 mg ropivacaine with 30 mg ketorolac was performed intraoperatively for knee arthroplasty. Serum creatinine was measured daily for the first 2 postoperative days. Patients were discharged once they met the criteria for discharge according to the ERAS program protocol and without decreasing serum creatinine levels compared with preoperative values.

We collected patients’ demographic data, including age, sex, body weight, and American Society of Anesthesiologists (ASA) status. The type of operation performed and the percentage of patients having preoperative nephrotoxic drugs - angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) - were retrieved. Patients’ preoperative baseline renal function was measured by the serum creatinine (sCr) level. To assess the severity and duration of postoperative AKI, serial renal function tests were performed for the first 2 postoperative days. If the results were noted to be deranged compared with the patient’s baseline value, further renal function tests were ordered until the baseline renal function test result was achieved. The incidences of postoperative AKI with and without celecoxib were measured. This was further analyzed for patients with and without preexisting renal impairment. The incidence of AKI during each postoperative day and during the entire hospitalization period was measured. AKI was defined by the Acute Kidney Injury Network (AKIN) classification: Stage 1 = sCr increase greater than or equal to 26.4 mmol/L or an increase of 1.5-2.0 times from baseline. Stage 2 = sCr increase 2.0–3.0 times from baseline. Stage 3 = sCr increase > 3.0 times or requiring dialysis.

Statistical analysis

Categorical variables were expressed as frequencies and percentages, which were compared using chi-squared tests. Continuous variables are summarized as the means ± SD and were compared using Student’s unpaired t test. The sample size was based on the existing patient number during the study period; thus, no sample size calculations were performed.

From 2018–2021, our institution performed 1077 hip and knee arthroplasties, of which 215 patients (20%) had preexisting renal impairment. One hundred patients out of 1077 hip and knee arthroplasties (9.3%) had postoperative AKI. Eight hundred eighty-eight patients (82.5%) were prescribed perioperative celecoxib as part of the standard multimodal analgesic protocol, while 189 patients (17.5%) were not prescribed perioperative celecoxib as part of the standard multimodal analgesic protocol (Fig. 1).

For those 888 patients with perioperative celecoxib, the percentage of preexisting renal impairment was 14.5%, while the percentage without preexisting renal impairment (normal renal function) was 85.5% (Fig. 1). For those 189 patients not taking perioperative celecoxib, the percentage of preexisting renal impairment was 45.5%, while the percentage without preexisting renal impairment (normal renal function) was 54.5% (Fig. 1).

Although there were significant differences in the type of arthroplasties performed for patients receiving perioperative celecoxib with preexisting renal impairment and normal renal function, there were no statistically significant differences in ASA status and percentage of preoperative ACEIs and ARBs (Table 1). Although there were significant differences in age and body weight for patients not receiving perioperative celecoxib with preexisting renal impairment and normal renal function, there were no statistically significant differences in ASA status and percentage of preoperative ACEI and ARB (Table 1).

Table 1

Patient Demographics, Type of Operations and Percentage of Patients Taking Preoperative Nephrotoxic Drugs - Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs)
Variable	Preexisting renal impairment	Preexisting normal renal function	p value
With celecoxib (n = 888)
N	129	759
Age (years)	69.6 ± 10.9 (25–92)	68.7 ± 11.2 (17–97)	0.379
Sex (%)
F	61.2% (79/129)	65.3% (496/759)	0.366
M	38.82% (50/129)	34.7% (263/759)
Body weight (kg)	66.1 ± 14.5 (39.6–101)	66.6 ± 13.8 (23.1–126)	0.708
ASA status (%)
I	0.8%^a (1/129)	9.9% (75/759)	0.937^a
II	45.0% (58/129)	36.2% (275/759)
III	50.4% (65/129)	49.0% (372/759)
IV	3.9% (5/129)	4.9% (37/759)
Operation type (%)
Knee	82.9% (107/129)	69.7% (529/759)	0.002^b
Hip	17.1% (22/129)	30.3% (230/759)
Preop ACEI/ARB (%)
Y	48.1% (62/129)	53.2% (404/759)	0.277
N	51.9% (67/129)	46.8% (355/759)
Without celecoxib (n = 189)
N	86	103
Age (years)	68.2 ± 10.5 (42–94)	71.8 ± 10.5 (42–92)	0.019^b
Sex (%)
F	62.8% (54/86)	66.0% (68/103)	0.794
M	37.2% (32/86)	34.0% (35/103)
Body weight (kg)	69.4 ± 14.5 (36.9–120)	64.3 ± 14.0 (38–100.7)	0.015^b
ASA status (%)
I	1.2% (1/86)	7.8% (8/103)	0.415^a
II	39.5% (34/86)	38.8% (40/103)
III	51.2% (44/86)	46.6% (48/103)
IV	8.1% (7/86)	6.8% (7/103)
Operation type (%)
Knee	74.4% (64/86)	68.9% (71/103)	0.406
Hip	25.6% (22/86)	31.1% (32/103)
Preop ACEI/ARB (%)
Y	52.3% (45/86)	46.6% (48/103)	0.433
N	47.7% (41/86)	53.4% (55/103)
Values are the mean ± SD (range) or %(n)
^ap value of the Chi-square test for testing the percentage of patients classified as ASA I-II between the 2 groups. ASA status distributions: ASA I-II is comprised of ASA I and ASA II and ASA III-IV is comprised of ASA III and ASA IV for testing.
^bSignificant difference between the 2 groups, p value less than the 0.05 is considered statistically significant.

For the 888 patients taking perioperative celecoxib, the incidence of postoperative AKI (rise in sCr of > 50% from baseline) was 5.6%, 5.5% and 1.8% from postoperative days 1–3, respectively (Table 2). For the 189 patients not taking perioperative celecoxib, the prevalence of postoperative AKI (rise in sCr of > 50% from baseline) was 4.8%, 5.5% and 5.9% from postoperative days 1–3, respectively (Table 2). All were statistically insignificant except on postoperative day 3, showing an even lower incidence for those taking celecoxib. The overall incidence of AKI during hospitalization in those taking perioperative celecoxib was 9.2%, while it was 9.5% in those not taking perioperative celecoxib. There was no statistically significant difference (Table 2). The odds ratio was 0.97 [95% CI: 0.57–1.65]. There was no association between perioperative celecoxib and postoperative AKI.

Table 2

Incidence of Postoperative AKI in Patients With and Without Perioperative Celecoxib
	With celecoxib	Without celecoxib
Postoperative day	Percentage of postoperative AKI		P value
POD1 (n = 1073)	5.6% (50/886^a)	4.8% (9/187^a)	0.651
POD2 (n = 1035)	5.5% (47/852)	5.5% (10/183)	0.978
POD3 (n = 430)	1.8% (6/329)	5.9% (6/101)	0.039^b
POD4 (n = 335)	1.2% (3/253)	2.4% (2/82)	0.599
POD5 (n = 175)	0.0% (0/128)	2.1% (1/47)	0.269
POD6 (n = 122)	0% (0/84)	0% (0/38)	1.000
Overall (n = 1077)	9.2% (82/888)	9.5% (18/189)	0.901
Proportion (in %) (number/total).
^a2 missing data entry.
^bSignificantly different in % of postoperative AKI between Celebrex taking and not taking at the 0.05 level.

Patients taking celecoxib (888 patients) were further divided into groups with and without preexisting renal impairment (normal renal function), and the incidence of postoperative AKI was compared. The results for postoperative AKI are summarized in Table 3. The overall incidence of postoperative AKI for those with and without preexisting renal impairment was 9.3% and 9.2%, respectively (Fig. 1). This was not statistically significant. The duration for AKI was 4 days in both groups and peaked at postoperative day 2 in those with preexisting renal impairment and postoperative day 1 in those without preexisting renal impairment (Table 3). Most of the involved AKI cases were stage 1 for both groups of patients with and without preexisting renal impairment (Tables 4).

Table 3

Incidence of Postoperative AKI in Patients Taking Celecoxib Peroperatively
	Overall	Preexisting renal impairment	Normal RFT
Postop day	Percentage of postoperative AKI			P value (preexisting vs. normal RFT)
POD1 (n = 886)	5.6% (50/886)	4.7% (6/129)	5.8% (44/757)	0.597
POD2 (n = 852)	5.5% (47/852)	7.1% (9/127)	5.2% (38/725)	0.401
POD3 (n = 329)	1.8% (6/329)	5.2% (3/58)	1.1% (3/271)	0.070
POD4 (n = 253)	1.2% (3/253)	2.0% (1/51)	1.0% (2/202)	0.493
POD5 (n = 128)	0.0% (0/128)	0% (0/35)	0% (0/93)	1.000
POD6 (n = 84)	0% (0/84)	0% (0/21)	0% (0/63)	1.000
Overall (n = 888)	9.2% (82/888)	9.3% (12/129)	9.2% (70/759)	0.977
Proportion (in %) of AKI (number/total).

Table 4. Postoperative AKI in Different Stages (in % and (n)) in Patients Receiving Celecoxib Perioperatively and With Preexisting Renal Impairment and With Normal Renal Function

Patients not taking celecoxib (189 patients) were further divided into groups with and without preexisting renal impairment, and the incidence of postoperative AKI was compared. The results for postoperative AKI are summarized in Table 5. The overall incidence of postoperative AKI for those with and without preexisting renal impairment was 11.6% and 7.8%, respectively (Table 5). This was not statistically significant. For those with preexisting renal impairment, the duration of AKI was 5 days and peaked at postoperative day 2. For those without preexisting renal impairment, the duration of AKI was 3 days and peaked at postoperative day 1 (Table 5). All AKI cases involved were stage 1 for both groups of patients with and without preexisting renal impairment (Tables 6).

Table 5. Incidence of Postoperative AKI in Patients Not Taking Celecoxib Perioperatively

Postop day	Percentage of postop AKI			P value (preexisting vs. normal RFT)
	Overall	Preexisting renal impairment	Normal renal function
POD1 (n = 187)	4.8% (9/187)	2.4% (2/85)	6.9% (7/102)	0.186
POD2 (n = 183)	5.5% (10/183)	8.3% (7/84)	3.0% (3/99)	0.190
POD3 (n = 101)	5.9% (6/101)	7.1% (4/56)	4.4% (2/45)	0.690
POD4 (n = 82)	2.4% (2/82)	4.9% (2/41)	0% (0/41)	0.494
POD5 (n = 47)	2.1% (1/47)	3.8% (1/26)	0% (0/21)	1.000
POD6 (n = 38)	0% (0/38)	0% (0/19)	0% (0/19)	1.000
Overall (n = 189)	9.5% (18/189)	11.6% (10/86)	7.8% (8/103)	0.368
Value (in %) of AKI (number/total)

Table 6. Postoperative AKI in Different Stages (in % and (n)) in Patients Not Receiving Celecoxib Perioperatively and With Preexisting Renal Impairment and With Normal Renal Function

This is the first retrospective study in which researchers comprehensively evaluated the effect of perioperative celecoxib as one of the standard multimodal analgesic protocols on the risk of postoperative AKI in terms of incidence, severity, duration and possible reversibility in patients with and without preexisting renal impairment.

AKI is a common postoperative complication with an average rate ranging from 1.6% -1.69% according to the Scottish Arthroplasty Project Annual Report 2011[23]. Non-steroid anti-inflammatory drugs (NSAIDs) have been regarded as potentially nephrotoxic and may contribute to postoperative AKI, especially in elderly patients with preexisting renal impairment.

Patient characteristics were quite homogenous in terms of ASA status and percentage of patients having preoperative ACEIs or ARBs among patients receiving perioperative celecoxib with and without preexisting renal impairment. Patient characteristics were also quite homogenous in terms of ASA status and percentage of patients having preoperative ACEIs or ARBs among patients not receiving perioperative celecoxib, with and without preexisting renal impairment.

We have shown that the overall incidence of AKI during hospitalization for those taking perioperative celecoxib was 9.2%, while it was 9.5% for those not taking perioperative celecoxib. There was no significant difference (Table 2). This implies that the use of perioperative celecoxib may not significantly contribute to postoperative AKI. The odds ratio for having perioperative celecoxib was 0.97 (< 1), suggesting that patients with perioperative celecoxib were 0.97 times (95% CI: 0.57–1.65) more likely to develop postoperative AKI than those without perioperative celecoxib. Therefore, no additional AKI risk was imposed on patients taking perioperative celecoxib.

To further evaluate the impact of perioperative celecoxib, it is essential to further investigate the incidence of AKI for those with preexisting renal impairment and those with normal renal function. We have shown that the overall incidence of postoperative AKI for those with preexisting renal impairment and with normal renal function was 9.3% and 9.2%, respectively. This was not statistically significant (Table 3). Our findings suggest that prescribing perioperative celecoxib in patients with preexisting renal impairment did not impose additional AKI risk. There was a similar pattern of AKI associated with preexisting renal impairment, and those with normal renal function – duration of AKI in both groups were in the first 4 postoperative days with; severity of AKI, which was grade 1 for both groups. This demonstrated similar reversibility and severity of AKI associated with perioperative celecoxib for both having preexisting renal impairment and normal renal function. Therefore, preexisting renal impairment was not a sole determining factor for not prescribing perioperative celecoxib. This is especially true if perioperative celecoxib is prescribed in short duration and in carefully selected patients with close monitoring of renal function test, urine output and fluid status.

After balancing the risks of celecoxib and the potential benefits of better pain control and shorter length of hospitalization, NSAIDs play an important role in multimodal analgesic protocols. Nevertheless, care should be taken for patients with risk factors for AKI, as shown in clinical studies ^10,13−22. These included advanced age, higher body mass index, hypertension, diabetes mellitus and preoperative use of nephrotoxic drugs, e.g., ACEIs and ARBs. Patients with increased risk should be closely monitored in terms of urine output and fluid intake with serial monitoring of renal function since the development of AKI is a known risk factor for future renal diseases[24].

We acknowledge the relatively small sample size of this study, single center and retrospective nature as the major limitations. The long-term effect of celecoxib beyond 6 days after the operation was not evaluated. It is also assumed that reversibility of renal function was achieved once the serum creatinine level returned to the patient’s baseline value. There are also several confounding factors of postoperative AKI instead of perioperative celecoxib alone, for example, preoperative use of nephrotoxic agents (e.g., ACEIs and ARBs), obesity, blood loss, urine output, intraoperative fluids and blood pressure as well as the heterogeneity of the types of surgical procedures involved, varying from primary to revision operations and from single knee arthroplasty to bilateral knee arthroplasty. This warrants further large-scale studies to further evaluate the impact of perioperative celecoxib and postoperative AKI. Moreover, comparison of pain control for those having and not having perioperative celecoxib should be evaluated to further justify the use of perioperative use of NSAIDs, balancing potential side effects and efficacy of NSAIDs.

As part of the multimodal analgesic protocol in an enhanced recovery program, 82.5% of our patients received perioperative celecoxib. In this retrospective clinical study of elective hip and knee arthroplasty, the overall postoperative AKI rate was 9.2% in patients taking perioperative celecoxib and 9.5% in those not taking perioperative celecoxib. There was no association between perioperative celecoxib and postoperative AKI. Patients taking perioperative celecoxib probably had no additional AKI risk. For those with perioperative celecoxib, the incidence of AKI was similar for those with preexisting renal impairment and for those with normal renal function. Most patients who developed AKI were cured by postoperative day 5. Appropriate risk stratification is still necessary in prescribing celecoxib for patients with preexisting renal impairment. It is generally safe to administer perioperative NSAIDs even with preexisting renal impairment provided that it is for a short duration with good perioperative fluid management and postoperative monitoring of renal function.

ACEIs Angiotensin converting enzyme inhibitors

AKI Acute kidney injury

AKIN Acute Kidney Injury Network

ARBs Angiotensin receptor blockers

ASA American Society of Anesthesiologists

COX-2 Cyclooxygenase-2

ERAS Enhanced recovery after surgery

LIA Local infiltration of anesthetics

NSAIDs Non-steroid anti-inflammatory drugs

OA Osteoarthritis

sCr Serum creatinine

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Zhongda Hospital of Southeast University (NO.2021ZDKYSB055). Written informed consent was exempted with the approval of the Ethics Committee. And all methods were performed in accordance with the relevant guidelines and regulations.

Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

Conflict of interest

The authors have no conflicts of interests to declare.

Funding

The present study was supported by the National Natural Science Foundation of China (Grant Numbers 81570043 and 82170063)

Author Contributions

Zhaoji Li and Ruifeng Zhang made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Acknowledgments

The authors thank all the participants in the study and the staff at the Zhongda hospital of Southeast University for their contribution in obtaining the data.

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No competing interests reported.

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Incidence, severity and reversibility of acute kidney injury after elective hip and knee arthroplasty in patients receiving celecoxib perioperatively as one of the standard multimodal analgesic protocols

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