Eileen Hennrikus, MD, FACP

We are pleased to note the response of Onuigbo et al. to our article demonstrating an increase in acute kidney injury (AKI) associated with angiotensin axis blockade (AAB) in major orthopedic surgery.[1] Like Onuigbo et al., we also noted that intraoperative hypotension and AAB are associated with AKI.[2] In addition, we found that AAB‐associated AKI occurred independently of intraoperative hypotension. Because of our findings, we withhold angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers on the day of surgery in all patients presenting for major orthopedic surgery whose blood pressure is well controlled preoperatively. We were concerned that this practice might increase the incidence of pre‐ and postoperative hypertension in such patients, but we have been reassured by a recent article demonstrating that this does not occur in outpatient surgical patients.[3]

We caution, however, that the common sense approach of stopping AAB preoperatively to avoid possible AKI still requires evaluation by a properly conducted randomized controlled trial. Because of the prolonged systemic half‐life and duration of tissue activity (>24 hours) of many AAB agents,[4] the required preoperative cessation period of AAB may vary considerably.

We are pleased to note the response of Onuigbo et al. to our article demonstrating an increase in acute kidney injury (AKI) associated with angiotensin axis blockade (AAB) in major orthopedic surgery.[1] Like Onuigbo et al., we also noted that intraoperative hypotension and AAB are associated with AKI.[2] In addition, we found that AAB‐associated AKI occurred independently of intraoperative hypotension. Because of our findings, we withhold angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers on the day of surgery in all patients presenting for major orthopedic surgery whose blood pressure is well controlled preoperatively. We were concerned that this practice might increase the incidence of pre‐ and postoperative hypertension in such patients, but we have been reassured by a recent article demonstrating that this does not occur in outpatient surgical patients.[3]

We caution, however, that the common sense approach of stopping AAB preoperatively to avoid possible AKI still requires evaluation by a properly conducted randomized controlled trial. Because of the prolonged systemic half‐life and duration of tissue activity (>24 hours) of many AAB agents,[4] the required preoperative cessation period of AAB may vary considerably.

We are pleased to note the response of Onuigbo et al. to our article demonstrating an increase in acute kidney injury (AKI) associated with angiotensin axis blockade (AAB) in major orthopedic surgery.[1] Like Onuigbo et al., we also noted that intraoperative hypotension and AAB are associated with AKI.[2] In addition, we found that AAB‐associated AKI occurred independently of intraoperative hypotension. Because of our findings, we withhold angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers on the day of surgery in all patients presenting for major orthopedic surgery whose blood pressure is well controlled preoperatively. We were concerned that this practice might increase the incidence of pre‐ and postoperative hypertension in such patients, but we have been reassured by a recent article demonstrating that this does not occur in outpatient surgical patients.[3]

We caution, however, that the common sense approach of stopping AAB preoperatively to avoid possible AKI still requires evaluation by a properly conducted randomized controlled trial. Because of the prolonged systemic half‐life and duration of tissue activity (>24 hours) of many AAB agents,[4] the required preoperative cessation period of AAB may vary considerably.

Patients presenting for surgery with angiotensin axis blockade (AAB) from therapy with either angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) experience an increased incidence of perioperative hypotension.[1, 2, 3, 4] Debate continues as to whether this hypotension results in any significant clinical sequelae. Some authors found that the use of an ACEI decreased the incidence of acute kidney injury (AKI),[5] mortality, and septicemia in cardiac and vascular surgical patients.[6] However, others found that in vascular and cardiac surgery there is increased mortality[7] as well as increased incidence of postoperative AKI.[8, 9, 10] A retrospective study of 10,000 coronary artery bypass graft patients found that ACEI was associated with increased inotropic support, AKI, mortality, and new onset atrial fibrillation.[11] In a meta‐analysis of 69,000 cardiothoracic surgery patients, the use of ACEIs/ARBs was associated with an increase in AKI and mortality.[12] AKI has also been demonstrated after lung resection surgery in patients receiving preoperative therapy with an ARB.[13]

Studies on noncardiac general surgery patients demonstrate that the use of AAB results in postinduction hypotension, but they fail to show an increased incidence in postoperative AKI.[14, 15] We propose, however, that major orthopedic surgery patients are a specific surgical cohort, like cardiac, vascular, and lung, who can develop operative hypotension and postoperative AKI when AAB is taken on the morning of surgery. To address this question we performed a retrospective study of 1154 patients undergoing either spinal fusion, total knee arthroplasty (TKA), or total hip arthroplasty (THA) during the 2010 calendar year in our academic medical center. We measured the incidence of postanesthesia induction hypotension, intraoperative hypotension, and postoperative AKI as it relates to the administration of AAB preoperatively.

MATERIALS AND METHODS

This study was a retrospective, observational investigation at a single, large academic hospital. The study design for chart review was approved by the institutional review board prior to data collection. Informed patient consent was not required for this retrospective study.

RESULTS

DISCUSSION

In this retrospective review of 922 patients presenting for major orthopedic surgery, we found that 343(37%) were receiving therapy with either ACEIs or ARBs. In such patients, we demonstrated a higher incidence of postinduction hypotension and an increased incidence of AKI. We further demonstrated that the development of AKI associated with AAB therapy was independent of hypotension occurring either postinduction or intraoperatively after incision.

Postinduction hypotension in patients receiving AAB was demonstrated to be 12.2% compared to 7.7% in patients not receiving this therapy. Hypotension after general anesthesia induction in patients receiving AAB is widely reported,[1, 14, 15] and ranges from 22% to 100%[19, 20] based on varying definitions of what constitutes hypotension. We chose an absolute value of a systolic blood pressure of 80 mm Hg occurring for 5 minutes as constituting significant hypotension.[16] Monk et al. reported an increased one year postnon‐cardiac surgery mortality risk of 1.036 times per minute of intraoperative hypotension, defining hypotension as a systolic blood pressure of <80 mm Hg.[21]

We further demonstrated that AAB therapy resulted in an 8.3% incidence of AKI versus 1.7% in non‐AAB patients (P<0.001). AKI was defined as an increase in serum creatinine of 0.3 mg/dL or a 50% increase in creatinine when pre‐ and postoperative values were compared.[17] A number of other investigators have identified AKI associated with AAB use in patients undergoing cardiac,[6, 11] vascular,[7, 10] and lung[13] surgery. Similarly, in the present study, in orthopedic patients, AAB remained a significant risk factor for developing AKI (OR: 2.68, P=0.034) independent of patient comorbidities and adjunct therapy (Table 2).

ACEIs and ARBs are prescribed to treat HTN, CHF, and improve renal function in diabetic and proteinuric nephropathy.[22] AAB therapy is prescribed for nephropathy because these medications decrease glomerular pressure by selective inhibition of angiotensin II mediated vasoconstriction of the efferent glomerular arteriole.[23] Normally, this is beneficial to patients and is associated with a decrease in serum creatinine concentration. However, during hypotension, when there is decreased renal perfusion, further decreases in intraglomerular pressure may occur, precipitating renal failure.[23] In addition, other factors may contribute to the development of AKI, as AAB has both tissue and systemic effects that extend beyond simply dilating the efferent glomerular arteriole. These include effects on the sympathetic nervous system, oxidative stress, and altering the release and synthesis of vasodilators such as bradykinin, nitric oxide, and prostacyclins[24] as well as effects through the release of aldosterone and arginine‐vasopressin.[25] These other factors might help explain the present study's findings that, when eliminating the effect of both postinduction and intraoperative hypotension, AAB therapy continued to have a statistically significant independent effect (OR: 2.60, 95% CI: 1.046.51, P=0.042) on developing postoperative AKI.

Although we demonstrated an association of AAB therapy with the development of hypotension after induction, we demonstrated only a trend in the development of postincisional, intraoperative hypotension (P=0.078). We defined intraoperative hypotension as a systolic BP <80 mm Hg for 10 minutes occurring after skin incision.[16] One must take into consideration, however, that a significant number of AAB patients were hypotensive during induction and received higher doses of ephedrine and vasopressin during the operative period. These patients may have been rescued from intraoperative hypotension by receiving vasopressor treatment at the outset. We did find that intraoperative hypotension was a significant, independent risk factor for AKI (OR: 2.62, P=0.019).

We looked further at the consequences of developing AKI. Patients who developed AKI had a significant greater mean length of hospital stay (5.76 days vs 3.28 days, P<0.001), which is consistent with other investigators' findings.[25, 26, 27] Although 2‐year mortality was higher at 5.88% in the AKI group compared to 2.38% in the non‐AAB group, this was not statistically significant (P=0.211). Other studies have shown that the development of AKI results in greater mortality.[26, 28]

The American College of Physicians (ACP) recommendations as of 2013 regarding the use of ACEIs and ARBs preoperatively is: uncertain, continue with caution, avoid hypovolemia. Potential for hypotension with induction of anesthesia and increased vasoconstrictor requirements and decreased responsiveness to pressors.[29] The ACP acknowledges that preoperative ACEIs and ARBs have the potential for postinduction hypotension and increased requirements for vasopressors. We have implemented recommendations at our preoperative anesthesia clinic to hold ACEIs and ARBs on the morning of surgery in patients with controlled blood pressure scheduled for spine fusion, and hip and knee arthroplasties. In accordance with ACP guidelines, other antihypertensives such as ‐blockers, calcium channel blockers, nitrates, and sympatholytics should be continued preoperatively and can be used perioperatively.

CONCLUSIONS

Patients who receive preoperative ACEI or ARB therapy and undergo major orthopedic surgery such as spinal fusion, and hip or knee arthroplasties experience a higher incidence of postinduction hypotension and AKI than those not receiving such therapy. The development of AKI in such patients is associated with a significantly prolonged length of hospital stay. Our findings suggest an association between preoperative ACEI/ARB use and moderate kidney injury following major orthopedic surgeries. However, a prospective, multicentered, randomized trial needs to be performed to confirm that withdrawal of AAB therapy preoperatively will decrease the incidence of AKI in patients undergoing major orthopedic procedures under general anesthesia. Future studies also need to determine the optimal time duration of withholding AAB therapy and the consequences on cardiac outcomes.

Patients presenting for surgery with angiotensin axis blockade (AAB) from therapy with either angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) experience an increased incidence of perioperative hypotension.[1, 2, 3, 4] Debate continues as to whether this hypotension results in any significant clinical sequelae. Some authors found that the use of an ACEI decreased the incidence of acute kidney injury (AKI),[5] mortality, and septicemia in cardiac and vascular surgical patients.[6] However, others found that in vascular and cardiac surgery there is increased mortality[7] as well as increased incidence of postoperative AKI.[8, 9, 10] A retrospective study of 10,000 coronary artery bypass graft patients found that ACEI was associated with increased inotropic support, AKI, mortality, and new onset atrial fibrillation.[11] In a meta‐analysis of 69,000 cardiothoracic surgery patients, the use of ACEIs/ARBs was associated with an increase in AKI and mortality.[12] AKI has also been demonstrated after lung resection surgery in patients receiving preoperative therapy with an ARB.[13]

Studies on noncardiac general surgery patients demonstrate that the use of AAB results in postinduction hypotension, but they fail to show an increased incidence in postoperative AKI.[14, 15] We propose, however, that major orthopedic surgery patients are a specific surgical cohort, like cardiac, vascular, and lung, who can develop operative hypotension and postoperative AKI when AAB is taken on the morning of surgery. To address this question we performed a retrospective study of 1154 patients undergoing either spinal fusion, total knee arthroplasty (TKA), or total hip arthroplasty (THA) during the 2010 calendar year in our academic medical center. We measured the incidence of postanesthesia induction hypotension, intraoperative hypotension, and postoperative AKI as it relates to the administration of AAB preoperatively.

MATERIALS AND METHODS

This study was a retrospective, observational investigation at a single, large academic hospital. The study design for chart review was approved by the institutional review board prior to data collection. Informed patient consent was not required for this retrospective study.

RESULTS

DISCUSSION

In this retrospective review of 922 patients presenting for major orthopedic surgery, we found that 343(37%) were receiving therapy with either ACEIs or ARBs. In such patients, we demonstrated a higher incidence of postinduction hypotension and an increased incidence of AKI. We further demonstrated that the development of AKI associated with AAB therapy was independent of hypotension occurring either postinduction or intraoperatively after incision.

Postinduction hypotension in patients receiving AAB was demonstrated to be 12.2% compared to 7.7% in patients not receiving this therapy. Hypotension after general anesthesia induction in patients receiving AAB is widely reported,[1, 14, 15] and ranges from 22% to 100%[19, 20] based on varying definitions of what constitutes hypotension. We chose an absolute value of a systolic blood pressure of 80 mm Hg occurring for 5 minutes as constituting significant hypotension.[16] Monk et al. reported an increased one year postnon‐cardiac surgery mortality risk of 1.036 times per minute of intraoperative hypotension, defining hypotension as a systolic blood pressure of <80 mm Hg.[21]

We further demonstrated that AAB therapy resulted in an 8.3% incidence of AKI versus 1.7% in non‐AAB patients (P<0.001). AKI was defined as an increase in serum creatinine of 0.3 mg/dL or a 50% increase in creatinine when pre‐ and postoperative values were compared.[17] A number of other investigators have identified AKI associated with AAB use in patients undergoing cardiac,[6, 11] vascular,[7, 10] and lung[13] surgery. Similarly, in the present study, in orthopedic patients, AAB remained a significant risk factor for developing AKI (OR: 2.68, P=0.034) independent of patient comorbidities and adjunct therapy (Table 2).

ACEIs and ARBs are prescribed to treat HTN, CHF, and improve renal function in diabetic and proteinuric nephropathy.[22] AAB therapy is prescribed for nephropathy because these medications decrease glomerular pressure by selective inhibition of angiotensin II mediated vasoconstriction of the efferent glomerular arteriole.[23] Normally, this is beneficial to patients and is associated with a decrease in serum creatinine concentration. However, during hypotension, when there is decreased renal perfusion, further decreases in intraglomerular pressure may occur, precipitating renal failure.[23] In addition, other factors may contribute to the development of AKI, as AAB has both tissue and systemic effects that extend beyond simply dilating the efferent glomerular arteriole. These include effects on the sympathetic nervous system, oxidative stress, and altering the release and synthesis of vasodilators such as bradykinin, nitric oxide, and prostacyclins[24] as well as effects through the release of aldosterone and arginine‐vasopressin.[25] These other factors might help explain the present study's findings that, when eliminating the effect of both postinduction and intraoperative hypotension, AAB therapy continued to have a statistically significant independent effect (OR: 2.60, 95% CI: 1.046.51, P=0.042) on developing postoperative AKI.

Although we demonstrated an association of AAB therapy with the development of hypotension after induction, we demonstrated only a trend in the development of postincisional, intraoperative hypotension (P=0.078). We defined intraoperative hypotension as a systolic BP <80 mm Hg for 10 minutes occurring after skin incision.[16] One must take into consideration, however, that a significant number of AAB patients were hypotensive during induction and received higher doses of ephedrine and vasopressin during the operative period. These patients may have been rescued from intraoperative hypotension by receiving vasopressor treatment at the outset. We did find that intraoperative hypotension was a significant, independent risk factor for AKI (OR: 2.62, P=0.019).

We looked further at the consequences of developing AKI. Patients who developed AKI had a significant greater mean length of hospital stay (5.76 days vs 3.28 days, P<0.001), which is consistent with other investigators' findings.[25, 26, 27] Although 2‐year mortality was higher at 5.88% in the AKI group compared to 2.38% in the non‐AAB group, this was not statistically significant (P=0.211). Other studies have shown that the development of AKI results in greater mortality.[26, 28]

The American College of Physicians (ACP) recommendations as of 2013 regarding the use of ACEIs and ARBs preoperatively is: uncertain, continue with caution, avoid hypovolemia. Potential for hypotension with induction of anesthesia and increased vasoconstrictor requirements and decreased responsiveness to pressors.[29] The ACP acknowledges that preoperative ACEIs and ARBs have the potential for postinduction hypotension and increased requirements for vasopressors. We have implemented recommendations at our preoperative anesthesia clinic to hold ACEIs and ARBs on the morning of surgery in patients with controlled blood pressure scheduled for spine fusion, and hip and knee arthroplasties. In accordance with ACP guidelines, other antihypertensives such as ‐blockers, calcium channel blockers, nitrates, and sympatholytics should be continued preoperatively and can be used perioperatively.

CONCLUSIONS

Patients who receive preoperative ACEI or ARB therapy and undergo major orthopedic surgery such as spinal fusion, and hip or knee arthroplasties experience a higher incidence of postinduction hypotension and AKI than those not receiving such therapy. The development of AKI in such patients is associated with a significantly prolonged length of hospital stay. Our findings suggest an association between preoperative ACEI/ARB use and moderate kidney injury following major orthopedic surgeries. However, a prospective, multicentered, randomized trial needs to be performed to confirm that withdrawal of AAB therapy preoperatively will decrease the incidence of AKI in patients undergoing major orthopedic procedures under general anesthesia. Future studies also need to determine the optimal time duration of withholding AAB therapy and the consequences on cardiac outcomes.

Patients presenting for surgery with angiotensin axis blockade (AAB) from therapy with either angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) experience an increased incidence of perioperative hypotension.[1, 2, 3, 4] Debate continues as to whether this hypotension results in any significant clinical sequelae. Some authors found that the use of an ACEI decreased the incidence of acute kidney injury (AKI),[5] mortality, and septicemia in cardiac and vascular surgical patients.[6] However, others found that in vascular and cardiac surgery there is increased mortality[7] as well as increased incidence of postoperative AKI.[8, 9, 10] A retrospective study of 10,000 coronary artery bypass graft patients found that ACEI was associated with increased inotropic support, AKI, mortality, and new onset atrial fibrillation.[11] In a meta‐analysis of 69,000 cardiothoracic surgery patients, the use of ACEIs/ARBs was associated with an increase in AKI and mortality.[12] AKI has also been demonstrated after lung resection surgery in patients receiving preoperative therapy with an ARB.[13]

Studies on noncardiac general surgery patients demonstrate that the use of AAB results in postinduction hypotension, but they fail to show an increased incidence in postoperative AKI.[14, 15] We propose, however, that major orthopedic surgery patients are a specific surgical cohort, like cardiac, vascular, and lung, who can develop operative hypotension and postoperative AKI when AAB is taken on the morning of surgery. To address this question we performed a retrospective study of 1154 patients undergoing either spinal fusion, total knee arthroplasty (TKA), or total hip arthroplasty (THA) during the 2010 calendar year in our academic medical center. We measured the incidence of postanesthesia induction hypotension, intraoperative hypotension, and postoperative AKI as it relates to the administration of AAB preoperatively.

MATERIALS AND METHODS

This study was a retrospective, observational investigation at a single, large academic hospital. The study design for chart review was approved by the institutional review board prior to data collection. Informed patient consent was not required for this retrospective study.

RESULTS

DISCUSSION

In this retrospective review of 922 patients presenting for major orthopedic surgery, we found that 343(37%) were receiving therapy with either ACEIs or ARBs. In such patients, we demonstrated a higher incidence of postinduction hypotension and an increased incidence of AKI. We further demonstrated that the development of AKI associated with AAB therapy was independent of hypotension occurring either postinduction or intraoperatively after incision.

Postinduction hypotension in patients receiving AAB was demonstrated to be 12.2% compared to 7.7% in patients not receiving this therapy. Hypotension after general anesthesia induction in patients receiving AAB is widely reported,[1, 14, 15] and ranges from 22% to 100%[19, 20] based on varying definitions of what constitutes hypotension. We chose an absolute value of a systolic blood pressure of 80 mm Hg occurring for 5 minutes as constituting significant hypotension.[16] Monk et al. reported an increased one year postnon‐cardiac surgery mortality risk of 1.036 times per minute of intraoperative hypotension, defining hypotension as a systolic blood pressure of <80 mm Hg.[21]

We further demonstrated that AAB therapy resulted in an 8.3% incidence of AKI versus 1.7% in non‐AAB patients (P<0.001). AKI was defined as an increase in serum creatinine of 0.3 mg/dL or a 50% increase in creatinine when pre‐ and postoperative values were compared.[17] A number of other investigators have identified AKI associated with AAB use in patients undergoing cardiac,[6, 11] vascular,[7, 10] and lung[13] surgery. Similarly, in the present study, in orthopedic patients, AAB remained a significant risk factor for developing AKI (OR: 2.68, P=0.034) independent of patient comorbidities and adjunct therapy (Table 2).

ACEIs and ARBs are prescribed to treat HTN, CHF, and improve renal function in diabetic and proteinuric nephropathy.[22] AAB therapy is prescribed for nephropathy because these medications decrease glomerular pressure by selective inhibition of angiotensin II mediated vasoconstriction of the efferent glomerular arteriole.[23] Normally, this is beneficial to patients and is associated with a decrease in serum creatinine concentration. However, during hypotension, when there is decreased renal perfusion, further decreases in intraglomerular pressure may occur, precipitating renal failure.[23] In addition, other factors may contribute to the development of AKI, as AAB has both tissue and systemic effects that extend beyond simply dilating the efferent glomerular arteriole. These include effects on the sympathetic nervous system, oxidative stress, and altering the release and synthesis of vasodilators such as bradykinin, nitric oxide, and prostacyclins[24] as well as effects through the release of aldosterone and arginine‐vasopressin.[25] These other factors might help explain the present study's findings that, when eliminating the effect of both postinduction and intraoperative hypotension, AAB therapy continued to have a statistically significant independent effect (OR: 2.60, 95% CI: 1.046.51, P=0.042) on developing postoperative AKI.

Although we demonstrated an association of AAB therapy with the development of hypotension after induction, we demonstrated only a trend in the development of postincisional, intraoperative hypotension (P=0.078). We defined intraoperative hypotension as a systolic BP <80 mm Hg for 10 minutes occurring after skin incision.[16] One must take into consideration, however, that a significant number of AAB patients were hypotensive during induction and received higher doses of ephedrine and vasopressin during the operative period. These patients may have been rescued from intraoperative hypotension by receiving vasopressor treatment at the outset. We did find that intraoperative hypotension was a significant, independent risk factor for AKI (OR: 2.62, P=0.019).

We looked further at the consequences of developing AKI. Patients who developed AKI had a significant greater mean length of hospital stay (5.76 days vs 3.28 days, P<0.001), which is consistent with other investigators' findings.[25, 26, 27] Although 2‐year mortality was higher at 5.88% in the AKI group compared to 2.38% in the non‐AAB group, this was not statistically significant (P=0.211). Other studies have shown that the development of AKI results in greater mortality.[26, 28]

The American College of Physicians (ACP) recommendations as of 2013 regarding the use of ACEIs and ARBs preoperatively is: uncertain, continue with caution, avoid hypovolemia. Potential for hypotension with induction of anesthesia and increased vasoconstrictor requirements and decreased responsiveness to pressors.[29] The ACP acknowledges that preoperative ACEIs and ARBs have the potential for postinduction hypotension and increased requirements for vasopressors. We have implemented recommendations at our preoperative anesthesia clinic to hold ACEIs and ARBs on the morning of surgery in patients with controlled blood pressure scheduled for spine fusion, and hip and knee arthroplasties. In accordance with ACP guidelines, other antihypertensives such as ‐blockers, calcium channel blockers, nitrates, and sympatholytics should be continued preoperatively and can be used perioperatively.

CONCLUSIONS

Patients who receive preoperative ACEI or ARB therapy and undergo major orthopedic surgery such as spinal fusion, and hip or knee arthroplasties experience a higher incidence of postinduction hypotension and AKI than those not receiving such therapy. The development of AKI in such patients is associated with a significantly prolonged length of hospital stay. Our findings suggest an association between preoperative ACEI/ARB use and moderate kidney injury following major orthopedic surgeries. However, a prospective, multicentered, randomized trial needs to be performed to confirm that withdrawal of AAB therapy preoperatively will decrease the incidence of AKI in patients undergoing major orthopedic procedures under general anesthesia. Future studies also need to determine the optimal time duration of withholding AAB therapy and the consequences on cardiac outcomes.