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In reply: A serious complication of a common stress test
In Reply: We appreciate the interest and comments of Dr. Alraies. We would like to clarify that the patient’s baseline electrocardiogram before the nuclear stress test was normal. Second-degree atrioventricular (AV) block (Mobitz type I) was evident only during adenosine infusion before ventricular asystole. The patient was on two AV nodal blockers (labetalol and clonidine) but had no underlying conduction disease. There is no contraindication to continuing these agents before pharmacologic stress testing. In addition, the patient’s electrolyte levels were within normal ranges before testing.
We agree that the valuable teaching point for clinicians is to appreciate the contraindication to and consequences of the use of dipyridamole-containing oral medications and either adenosine or regadenoson during pharmacologic stress testing. As Dr. Alraies points out, most cardiologists may be familiar with this interaction, but a large proportion of stress tests are ordered by emergency room physicians, internists, and hospitalists who are not. Still, the overall incidence of side effects with pharmacologic stress testing is very low and comparable to that with exercise testing, with safety enhanced by following the American Society of Nuclear Cardiology (ASNC) guidelines for performing stress myocardial perfusion imaging.1 Avoidance of this interaction may be enhanced through education, but also by using checklists and building notifications into the electronic medical record when ordering pharmacologic stress testing. Of note, according to the ASNC guidelines, the use of intravenous dipyridamole as a stress agent is a safe alternative for pharmacologic stress testing in patients taking oral dipyridamole-containing medications.
- Henzlova MJ, Cerqueira MD, Mahmarian JJ, Yao SS; Quality Assurance Committee of the American Society of Nuclear Cardiology. Stress protocols and tracers. J Nucl Cardiol 2006; 13:e80–e90.
In Reply: We appreciate the interest and comments of Dr. Alraies. We would like to clarify that the patient’s baseline electrocardiogram before the nuclear stress test was normal. Second-degree atrioventricular (AV) block (Mobitz type I) was evident only during adenosine infusion before ventricular asystole. The patient was on two AV nodal blockers (labetalol and clonidine) but had no underlying conduction disease. There is no contraindication to continuing these agents before pharmacologic stress testing. In addition, the patient’s electrolyte levels were within normal ranges before testing.
We agree that the valuable teaching point for clinicians is to appreciate the contraindication to and consequences of the use of dipyridamole-containing oral medications and either adenosine or regadenoson during pharmacologic stress testing. As Dr. Alraies points out, most cardiologists may be familiar with this interaction, but a large proportion of stress tests are ordered by emergency room physicians, internists, and hospitalists who are not. Still, the overall incidence of side effects with pharmacologic stress testing is very low and comparable to that with exercise testing, with safety enhanced by following the American Society of Nuclear Cardiology (ASNC) guidelines for performing stress myocardial perfusion imaging.1 Avoidance of this interaction may be enhanced through education, but also by using checklists and building notifications into the electronic medical record when ordering pharmacologic stress testing. Of note, according to the ASNC guidelines, the use of intravenous dipyridamole as a stress agent is a safe alternative for pharmacologic stress testing in patients taking oral dipyridamole-containing medications.
In Reply: We appreciate the interest and comments of Dr. Alraies. We would like to clarify that the patient’s baseline electrocardiogram before the nuclear stress test was normal. Second-degree atrioventricular (AV) block (Mobitz type I) was evident only during adenosine infusion before ventricular asystole. The patient was on two AV nodal blockers (labetalol and clonidine) but had no underlying conduction disease. There is no contraindication to continuing these agents before pharmacologic stress testing. In addition, the patient’s electrolyte levels were within normal ranges before testing.
We agree that the valuable teaching point for clinicians is to appreciate the contraindication to and consequences of the use of dipyridamole-containing oral medications and either adenosine or regadenoson during pharmacologic stress testing. As Dr. Alraies points out, most cardiologists may be familiar with this interaction, but a large proportion of stress tests are ordered by emergency room physicians, internists, and hospitalists who are not. Still, the overall incidence of side effects with pharmacologic stress testing is very low and comparable to that with exercise testing, with safety enhanced by following the American Society of Nuclear Cardiology (ASNC) guidelines for performing stress myocardial perfusion imaging.1 Avoidance of this interaction may be enhanced through education, but also by using checklists and building notifications into the electronic medical record when ordering pharmacologic stress testing. Of note, according to the ASNC guidelines, the use of intravenous dipyridamole as a stress agent is a safe alternative for pharmacologic stress testing in patients taking oral dipyridamole-containing medications.
- Henzlova MJ, Cerqueira MD, Mahmarian JJ, Yao SS; Quality Assurance Committee of the American Society of Nuclear Cardiology. Stress protocols and tracers. J Nucl Cardiol 2006; 13:e80–e90.
- Henzlova MJ, Cerqueira MD, Mahmarian JJ, Yao SS; Quality Assurance Committee of the American Society of Nuclear Cardiology. Stress protocols and tracers. J Nucl Cardiol 2006; 13:e80–e90.
Letter to the Editor
McCausland and colleagues[1] have published an excellent study on the association of dysnatremia with morbidity and mortality in patients undergoing major orthopedic surgery, which found that it was associated with greater mortality. However, we have some concerns regarding the article and wish to share them.
First, what is the definition of major orthopedic surgery? The authors did not give us a criterion. In our opinion, internal or femoral neck fracture belongs to minor orthopedic surgery, but such fractures usually occurs in patients older than 65 years, who have a higher incidence of perioperative hyponatremia. Therefore, a detailed definition of major orthopedic surgery was needed in this article.
Second, the sample in this study included individuals aged 18 years and was not limited to individuals with fractures. However, as we know, young patients are usually healthy and without dysnatremia except for multiple fractures. Those with multiple fractures also have a higher chance of hyponatremia and higher mortality, mainly caused by the trauma itself. We think such confounding factors could affect the validity of this article.
- , , . Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery. J Hosp Med. 2014;9(5):297–302.
McCausland and colleagues[1] have published an excellent study on the association of dysnatremia with morbidity and mortality in patients undergoing major orthopedic surgery, which found that it was associated with greater mortality. However, we have some concerns regarding the article and wish to share them.
First, what is the definition of major orthopedic surgery? The authors did not give us a criterion. In our opinion, internal or femoral neck fracture belongs to minor orthopedic surgery, but such fractures usually occurs in patients older than 65 years, who have a higher incidence of perioperative hyponatremia. Therefore, a detailed definition of major orthopedic surgery was needed in this article.
Second, the sample in this study included individuals aged 18 years and was not limited to individuals with fractures. However, as we know, young patients are usually healthy and without dysnatremia except for multiple fractures. Those with multiple fractures also have a higher chance of hyponatremia and higher mortality, mainly caused by the trauma itself. We think such confounding factors could affect the validity of this article.
McCausland and colleagues[1] have published an excellent study on the association of dysnatremia with morbidity and mortality in patients undergoing major orthopedic surgery, which found that it was associated with greater mortality. However, we have some concerns regarding the article and wish to share them.
First, what is the definition of major orthopedic surgery? The authors did not give us a criterion. In our opinion, internal or femoral neck fracture belongs to minor orthopedic surgery, but such fractures usually occurs in patients older than 65 years, who have a higher incidence of perioperative hyponatremia. Therefore, a detailed definition of major orthopedic surgery was needed in this article.
Second, the sample in this study included individuals aged 18 years and was not limited to individuals with fractures. However, as we know, young patients are usually healthy and without dysnatremia except for multiple fractures. Those with multiple fractures also have a higher chance of hyponatremia and higher mortality, mainly caused by the trauma itself. We think such confounding factors could affect the validity of this article.
- , , . Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery. J Hosp Med. 2014;9(5):297–302.
- , , . Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery. J Hosp Med. 2014;9(5):297–302.
Letter to the Editor
We thank Drs. Liu and Zhang for their letter and comments. Each diagnostic code in our dataset was individually reviewed by a board‐certified senior orthopedic surgeon (Dr. Wright). We considered procedures as major if they were of long duration, had the potential for significant blood loss, or represented major physiologic stress, including significant fluid balance requirements, in the opinion of our orthopedist coauthor. This set of diagnoses did include femoral neck fractures.
In our original analyses, we included fracture as a covariate in all statistical models and subsequently performed subgroup analyses according to the presence or absence of a diagnosis of fracture. As reported in our article,[1] J‐shaped associations of dysnatremia with greater length of stay were evident in those with and without fractures. In the 30‐day mortality analyses, only mild hyponatremia and hypernatremia remained associated with greater mortality in those with fracture. In those without a diagnosis of fracture, only moderate/severe hyponatremia remained associated with greater 30‐day mortality.
To assess for differences in associations of hyponatremia with outcomes according to age, we dichotomized this variable into those <65 years old versus 65 years old. We then fit model 3 from our original article to determine the adjusted effect estimates for length of stay and 30‐day mortality (Tables 1 and 2, respectively).
While the associations of dysnatremia with 30‐day mortality did not reach statistical significance in the <65 years age group, these results must be interpreted with caution due to the low number of events (35 deaths). We did not perform smaller subgroups analyses according to fracture type due to concerns of multiple comparisons testing, loss of statistical power, and inaccurate interpretation of effect estimates.
| Difference (95% CI) in Length of Stay in Days According to Category of Perioperative SNa | ||||
|---|---|---|---|---|
| 130 mmol/L, n=198 | 131134 mmol/L, n=1,036) | 135143 mmol/L, n=14,563 | 144 mmol/L, n=409 | |
| ||||
| Model 3 | ||||
| <65 years old | 2.3 (1.63.3), P<0.001 | 1.4 (1.21.6), P<0.001 | Ref | 1.5 (1.31.8), P<0.001 |
| 65 years old | 1.4 (1.11.7), P=0.001 | 1.4 (1.21.5), P<0.001 | Ref | 1.3 (1.11.5), P=0.002 |
| Hazard Ratio (95% CI) for 30‐Day Mortality According to Category of Perioperative SNa | ||||
|---|---|---|---|---|
| 130 mmol/L, n=198 | 131134 mmol/L, n=1,036 | 135143 mmol/L, n=14,563 | 144 mmol/L, n=409 | |
| ||||
| Model 3 | ||||
| <65 years old | 1.36 (0.7710.2), P=0.77 | 2.19 (0.935.19), P=0.07 | Ref | 4.17 (0.9718.0), P=0.06 |
| 65 years old | 2.44 (1.274.69), P=0.008 | 1.64 (1.052.55), P=0.03 | Ref | 2.98 (1.725.15), P<0.001 |
- , , . Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery. J Hosp Med. 2014;9(5):297–302.
We thank Drs. Liu and Zhang for their letter and comments. Each diagnostic code in our dataset was individually reviewed by a board‐certified senior orthopedic surgeon (Dr. Wright). We considered procedures as major if they were of long duration, had the potential for significant blood loss, or represented major physiologic stress, including significant fluid balance requirements, in the opinion of our orthopedist coauthor. This set of diagnoses did include femoral neck fractures.
In our original analyses, we included fracture as a covariate in all statistical models and subsequently performed subgroup analyses according to the presence or absence of a diagnosis of fracture. As reported in our article,[1] J‐shaped associations of dysnatremia with greater length of stay were evident in those with and without fractures. In the 30‐day mortality analyses, only mild hyponatremia and hypernatremia remained associated with greater mortality in those with fracture. In those without a diagnosis of fracture, only moderate/severe hyponatremia remained associated with greater 30‐day mortality.
To assess for differences in associations of hyponatremia with outcomes according to age, we dichotomized this variable into those <65 years old versus 65 years old. We then fit model 3 from our original article to determine the adjusted effect estimates for length of stay and 30‐day mortality (Tables 1 and 2, respectively).
While the associations of dysnatremia with 30‐day mortality did not reach statistical significance in the <65 years age group, these results must be interpreted with caution due to the low number of events (35 deaths). We did not perform smaller subgroups analyses according to fracture type due to concerns of multiple comparisons testing, loss of statistical power, and inaccurate interpretation of effect estimates.
| Difference (95% CI) in Length of Stay in Days According to Category of Perioperative SNa | ||||
|---|---|---|---|---|
| 130 mmol/L, n=198 | 131134 mmol/L, n=1,036) | 135143 mmol/L, n=14,563 | 144 mmol/L, n=409 | |
| ||||
| Model 3 | ||||
| <65 years old | 2.3 (1.63.3), P<0.001 | 1.4 (1.21.6), P<0.001 | Ref | 1.5 (1.31.8), P<0.001 |
| 65 years old | 1.4 (1.11.7), P=0.001 | 1.4 (1.21.5), P<0.001 | Ref | 1.3 (1.11.5), P=0.002 |
| Hazard Ratio (95% CI) for 30‐Day Mortality According to Category of Perioperative SNa | ||||
|---|---|---|---|---|
| 130 mmol/L, n=198 | 131134 mmol/L, n=1,036 | 135143 mmol/L, n=14,563 | 144 mmol/L, n=409 | |
| ||||
| Model 3 | ||||
| <65 years old | 1.36 (0.7710.2), P=0.77 | 2.19 (0.935.19), P=0.07 | Ref | 4.17 (0.9718.0), P=0.06 |
| 65 years old | 2.44 (1.274.69), P=0.008 | 1.64 (1.052.55), P=0.03 | Ref | 2.98 (1.725.15), P<0.001 |
We thank Drs. Liu and Zhang for their letter and comments. Each diagnostic code in our dataset was individually reviewed by a board‐certified senior orthopedic surgeon (Dr. Wright). We considered procedures as major if they were of long duration, had the potential for significant blood loss, or represented major physiologic stress, including significant fluid balance requirements, in the opinion of our orthopedist coauthor. This set of diagnoses did include femoral neck fractures.
In our original analyses, we included fracture as a covariate in all statistical models and subsequently performed subgroup analyses according to the presence or absence of a diagnosis of fracture. As reported in our article,[1] J‐shaped associations of dysnatremia with greater length of stay were evident in those with and without fractures. In the 30‐day mortality analyses, only mild hyponatremia and hypernatremia remained associated with greater mortality in those with fracture. In those without a diagnosis of fracture, only moderate/severe hyponatremia remained associated with greater 30‐day mortality.
To assess for differences in associations of hyponatremia with outcomes according to age, we dichotomized this variable into those <65 years old versus 65 years old. We then fit model 3 from our original article to determine the adjusted effect estimates for length of stay and 30‐day mortality (Tables 1 and 2, respectively).
While the associations of dysnatremia with 30‐day mortality did not reach statistical significance in the <65 years age group, these results must be interpreted with caution due to the low number of events (35 deaths). We did not perform smaller subgroups analyses according to fracture type due to concerns of multiple comparisons testing, loss of statistical power, and inaccurate interpretation of effect estimates.
| Difference (95% CI) in Length of Stay in Days According to Category of Perioperative SNa | ||||
|---|---|---|---|---|
| 130 mmol/L, n=198 | 131134 mmol/L, n=1,036) | 135143 mmol/L, n=14,563 | 144 mmol/L, n=409 | |
| ||||
| Model 3 | ||||
| <65 years old | 2.3 (1.63.3), P<0.001 | 1.4 (1.21.6), P<0.001 | Ref | 1.5 (1.31.8), P<0.001 |
| 65 years old | 1.4 (1.11.7), P=0.001 | 1.4 (1.21.5), P<0.001 | Ref | 1.3 (1.11.5), P=0.002 |
| Hazard Ratio (95% CI) for 30‐Day Mortality According to Category of Perioperative SNa | ||||
|---|---|---|---|---|
| 130 mmol/L, n=198 | 131134 mmol/L, n=1,036 | 135143 mmol/L, n=14,563 | 144 mmol/L, n=409 | |
| ||||
| Model 3 | ||||
| <65 years old | 1.36 (0.7710.2), P=0.77 | 2.19 (0.935.19), P=0.07 | Ref | 4.17 (0.9718.0), P=0.06 |
| 65 years old | 2.44 (1.274.69), P=0.008 | 1.64 (1.052.55), P=0.03 | Ref | 2.98 (1.725.15), P<0.001 |
- , , . Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery. J Hosp Med. 2014;9(5):297–302.
- , , . Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery. J Hosp Med. 2014;9(5):297–302.
Preoperative angiotensin axis blockade therapy, intraoperative hypotension, and the risks of postoperative acute kidney injury
We read with interest the analysis by Nielson et al., which concluded that patients undergoing major elective orthopedic surgery, who receive preoperative angiotensin axis blockade (AAB) therapy, have an associated increased risk of postinduction hypotension and postoperative acute kidney injury (AKI), with greater hospital length of stay.[1] We could not agree more with this conclusion.
Recently, we reported in the British Medical Journal our experiences with 2 patients who developed moderately severe AKI following surgical procedures while on concurrent AAB therapy, which led to prolonged hospital stays.[2, 3] The second patient was a 46‐year‐old obese Caucasian hypertensive male on triple‐whammy medications who developed intraoperative hypotension following an elective right‐hip arthroplasty.[3] Baseline serum creatinine more than doubled to 2.58 mg/dL within 36 hours. Hospital stay was prolonged. He improved with treatment before discharge.[3] We dubbed a new syndrome of quadruple whammy to represent perioperative AKI following intraoperative hypotension in patients on concurrent triple whammy medications.[2, 3]
We therefore support calls for the preemptive withholding of AAB before major elective surgical procedures, especially cardiovascular and orthopedic ones.[4] This is the cornerstone of a preventative nephrology paradigm called renoprevention, which we have repeatedly espoused since 2009.[5]
- , , , . Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9(5):283–288.
- , . “Quadruple whammy,” a new syndrome of potentially preventable yet iatrogenic acute kidney injury in the ICU. BMJ 2013: Rapid Response, Published online February 25, 2013. http://www.bmj.com/content/346/bmj.f678/rr/632570.
- , . A second case of “quadruple whammy” in a week in a northwestern Wisconsin hospital. BMJ. 2013: Rapid Response, Published online March 1, 2013. http://www.bmj.com/content/346/bmj.f678/rr/633687.
- , , , , , . Acute kidney injury and death associated with renin angiotensin system blockade in cardiothoracic surgery: a meta‐analysis of observational studies. Am J Kidney Dis. 2013;62(6):1077–1086.
- . Reno‐prevention vs. reno‐protection: a critical re‐appraisal of the evidence‐base from the large RAAS blockade trials after ONTARGET—a call for more circumspection. QJM. 2009;102:155–167.
We read with interest the analysis by Nielson et al., which concluded that patients undergoing major elective orthopedic surgery, who receive preoperative angiotensin axis blockade (AAB) therapy, have an associated increased risk of postinduction hypotension and postoperative acute kidney injury (AKI), with greater hospital length of stay.[1] We could not agree more with this conclusion.
Recently, we reported in the British Medical Journal our experiences with 2 patients who developed moderately severe AKI following surgical procedures while on concurrent AAB therapy, which led to prolonged hospital stays.[2, 3] The second patient was a 46‐year‐old obese Caucasian hypertensive male on triple‐whammy medications who developed intraoperative hypotension following an elective right‐hip arthroplasty.[3] Baseline serum creatinine more than doubled to 2.58 mg/dL within 36 hours. Hospital stay was prolonged. He improved with treatment before discharge.[3] We dubbed a new syndrome of quadruple whammy to represent perioperative AKI following intraoperative hypotension in patients on concurrent triple whammy medications.[2, 3]
We therefore support calls for the preemptive withholding of AAB before major elective surgical procedures, especially cardiovascular and orthopedic ones.[4] This is the cornerstone of a preventative nephrology paradigm called renoprevention, which we have repeatedly espoused since 2009.[5]
We read with interest the analysis by Nielson et al., which concluded that patients undergoing major elective orthopedic surgery, who receive preoperative angiotensin axis blockade (AAB) therapy, have an associated increased risk of postinduction hypotension and postoperative acute kidney injury (AKI), with greater hospital length of stay.[1] We could not agree more with this conclusion.
Recently, we reported in the British Medical Journal our experiences with 2 patients who developed moderately severe AKI following surgical procedures while on concurrent AAB therapy, which led to prolonged hospital stays.[2, 3] The second patient was a 46‐year‐old obese Caucasian hypertensive male on triple‐whammy medications who developed intraoperative hypotension following an elective right‐hip arthroplasty.[3] Baseline serum creatinine more than doubled to 2.58 mg/dL within 36 hours. Hospital stay was prolonged. He improved with treatment before discharge.[3] We dubbed a new syndrome of quadruple whammy to represent perioperative AKI following intraoperative hypotension in patients on concurrent triple whammy medications.[2, 3]
We therefore support calls for the preemptive withholding of AAB before major elective surgical procedures, especially cardiovascular and orthopedic ones.[4] This is the cornerstone of a preventative nephrology paradigm called renoprevention, which we have repeatedly espoused since 2009.[5]
- , , , . Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9(5):283–288.
- , . “Quadruple whammy,” a new syndrome of potentially preventable yet iatrogenic acute kidney injury in the ICU. BMJ 2013: Rapid Response, Published online February 25, 2013. http://www.bmj.com/content/346/bmj.f678/rr/632570.
- , . A second case of “quadruple whammy” in a week in a northwestern Wisconsin hospital. BMJ. 2013: Rapid Response, Published online March 1, 2013. http://www.bmj.com/content/346/bmj.f678/rr/633687.
- , , , , , . Acute kidney injury and death associated with renin angiotensin system blockade in cardiothoracic surgery: a meta‐analysis of observational studies. Am J Kidney Dis. 2013;62(6):1077–1086.
- . Reno‐prevention vs. reno‐protection: a critical re‐appraisal of the evidence‐base from the large RAAS blockade trials after ONTARGET—a call for more circumspection. QJM. 2009;102:155–167.
- , , , . Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9(5):283–288.
- , . “Quadruple whammy,” a new syndrome of potentially preventable yet iatrogenic acute kidney injury in the ICU. BMJ 2013: Rapid Response, Published online February 25, 2013. http://www.bmj.com/content/346/bmj.f678/rr/632570.
- , . A second case of “quadruple whammy” in a week in a northwestern Wisconsin hospital. BMJ. 2013: Rapid Response, Published online March 1, 2013. http://www.bmj.com/content/346/bmj.f678/rr/633687.
- , , , , , . Acute kidney injury and death associated with renin angiotensin system blockade in cardiothoracic surgery: a meta‐analysis of observational studies. Am J Kidney Dis. 2013;62(6):1077–1086.
- . Reno‐prevention vs. reno‐protection: a critical re‐appraisal of the evidence‐base from the large RAAS blockade trials after ONTARGET—a call for more circumspection. QJM. 2009;102:155–167.
In response to “Preoperative angiotensin axis blockade therapy, intraoperative hypotension, and the risks of postoperative acute kidney injury”
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.
- , , , . Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9:283–288.
- , . A second case of “quadruple whammy” in a week in a northwestern Wisconsin hospital. BMJ. 2013;346:f678.
- , , , . The risk of hypertension after preoperative discontinuation of angiotensin‐converting enzyme inhibitors or angiotensin receptor antagonists in ambulatory and same‐day admission patients. Anesth Analg. 2014;118:938–944.
- . Management of hypotension associated with angiotensin‐axis blockade and general anesthesia administration. J Cardiothorac Vasc Anesth. 2013;27:156–167.
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.
- , , , . Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9:283–288.
- , . A second case of “quadruple whammy” in a week in a northwestern Wisconsin hospital. BMJ. 2013;346:f678.
- , , , . The risk of hypertension after preoperative discontinuation of angiotensin‐converting enzyme inhibitors or angiotensin receptor antagonists in ambulatory and same‐day admission patients. Anesth Analg. 2014;118:938–944.
- . Management of hypotension associated with angiotensin‐axis blockade and general anesthesia administration. J Cardiothorac Vasc Anesth. 2013;27:156–167.
- , , , . Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9:283–288.
- , . A second case of “quadruple whammy” in a week in a northwestern Wisconsin hospital. BMJ. 2013;346:f678.
- , , , . The risk of hypertension after preoperative discontinuation of angiotensin‐converting enzyme inhibitors or angiotensin receptor antagonists in ambulatory and same‐day admission patients. Anesth Analg. 2014;118:938–944.
- . Management of hypotension associated with angiotensin‐axis blockade and general anesthesia administration. J Cardiothorac Vasc Anesth. 2013;27:156–167.
Insulin before surgery
To the Editor: We appreciated the thoughtful 1-Minute Consult by Drs. Dobri and Lansang, “How should we manage insulin therapy before surgery?”1 We agree with them in regard to the benefits of perioperative control of blood glucose levels. However, we disagree in general with their assertion that the full dose of the patient’s home dose of basal insulin be administered while the patient is nil per os (NPO) before surgery, with a reduction to 75% of the home dose only if the patient has a history of hypoglycemia, a recommendation that did not differentiate between patients with type 1 and type 2 diabetes mellitus.
The RABBIT 2 Surgery trial,2 which showed superiority of basal-bolus insulin over sliding scale insulin in surgical patients with type 2 diabetes mellitus, also showed a surprisingly high rate of hypoglycemia—24 (23.1%) of 104 patients had blood glucose levels lower than 70 mg/dL, compared with a similar trial in nonsurgical patients in which 2 (3.1%) of 65 patients had a blood glucose level less than 60 mg/dL.3 The authors of the two studies explained2 that “differences in hypoglycemic events between the two trials could be in part explained by reduced nutritional intake in surgical patients…”
Although patients with well-controlled type 1 diabetes mellitus may tolerate their full dose of basal insulin while NPO, we contend that patients with type 2 diabetes mellitus should be prescribed a reduced dose of basal insulin while NPO, regardless of the dose distribution or the patient’s overall glycemic control. It is routine practice on our consult service to reduce the basal insulin dose in such patients by roughly half.
- Dobri GA, Lansang MC. How should we manage insulin therapy before surgery? Cleve Clin J Med 2013; 80:702–704.
- Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011; 34:256–261.
- Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care 2007; 30:2181–2186.
To the Editor: We appreciated the thoughtful 1-Minute Consult by Drs. Dobri and Lansang, “How should we manage insulin therapy before surgery?”1 We agree with them in regard to the benefits of perioperative control of blood glucose levels. However, we disagree in general with their assertion that the full dose of the patient’s home dose of basal insulin be administered while the patient is nil per os (NPO) before surgery, with a reduction to 75% of the home dose only if the patient has a history of hypoglycemia, a recommendation that did not differentiate between patients with type 1 and type 2 diabetes mellitus.
The RABBIT 2 Surgery trial,2 which showed superiority of basal-bolus insulin over sliding scale insulin in surgical patients with type 2 diabetes mellitus, also showed a surprisingly high rate of hypoglycemia—24 (23.1%) of 104 patients had blood glucose levels lower than 70 mg/dL, compared with a similar trial in nonsurgical patients in which 2 (3.1%) of 65 patients had a blood glucose level less than 60 mg/dL.3 The authors of the two studies explained2 that “differences in hypoglycemic events between the two trials could be in part explained by reduced nutritional intake in surgical patients…”
Although patients with well-controlled type 1 diabetes mellitus may tolerate their full dose of basal insulin while NPO, we contend that patients with type 2 diabetes mellitus should be prescribed a reduced dose of basal insulin while NPO, regardless of the dose distribution or the patient’s overall glycemic control. It is routine practice on our consult service to reduce the basal insulin dose in such patients by roughly half.
To the Editor: We appreciated the thoughtful 1-Minute Consult by Drs. Dobri and Lansang, “How should we manage insulin therapy before surgery?”1 We agree with them in regard to the benefits of perioperative control of blood glucose levels. However, we disagree in general with their assertion that the full dose of the patient’s home dose of basal insulin be administered while the patient is nil per os (NPO) before surgery, with a reduction to 75% of the home dose only if the patient has a history of hypoglycemia, a recommendation that did not differentiate between patients with type 1 and type 2 diabetes mellitus.
The RABBIT 2 Surgery trial,2 which showed superiority of basal-bolus insulin over sliding scale insulin in surgical patients with type 2 diabetes mellitus, also showed a surprisingly high rate of hypoglycemia—24 (23.1%) of 104 patients had blood glucose levels lower than 70 mg/dL, compared with a similar trial in nonsurgical patients in which 2 (3.1%) of 65 patients had a blood glucose level less than 60 mg/dL.3 The authors of the two studies explained2 that “differences in hypoglycemic events between the two trials could be in part explained by reduced nutritional intake in surgical patients…”
Although patients with well-controlled type 1 diabetes mellitus may tolerate their full dose of basal insulin while NPO, we contend that patients with type 2 diabetes mellitus should be prescribed a reduced dose of basal insulin while NPO, regardless of the dose distribution or the patient’s overall glycemic control. It is routine practice on our consult service to reduce the basal insulin dose in such patients by roughly half.
- Dobri GA, Lansang MC. How should we manage insulin therapy before surgery? Cleve Clin J Med 2013; 80:702–704.
- Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011; 34:256–261.
- Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care 2007; 30:2181–2186.
- Dobri GA, Lansang MC. How should we manage insulin therapy before surgery? Cleve Clin J Med 2013; 80:702–704.
- Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011; 34:256–261.
- Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care 2007; 30:2181–2186.
In reply: Insulin before surgery
In Reply: We appreciate the kind words of Drs. Ditch and Moore, as well as their opinion.
Our article was intentionally brief—a 1-Minute Consult—and so could not cover all specific situations we encounter in clinical practice. We meant only to provide a general approach in this matter.
Quite often before surgery, patients receive less basal insulin than needed, or none at all, rather than too much. It has to be borne in mind that perioperative hyperglycemia—not just hypoglycemia—is linked with poor outcomes in cardiac1 and noncardiac surgery.2,3
Through our scenarios and suggestions, we have taken steps to err on the side of preventing hypoglycemia while averting hyperglycemia, at the same time making it easy to calculate the dose. In a scenario in which the basal insulin dose is about the same as the total of the prandial boluses, we have not yet seen evidence that raises concern for hypoglycemia, maybe because many of the patients with type 2 diabetes seen in our institution for surgery take, in addition to insulin, oral agents or noninsulin injections (which are appropriately withheld before surgery), and have suboptimal glycemic control on their home regimen. But if a physician has concerns for hypoglycemia, a dose reduction should be made.
There were some differences between the RABBIT 2 trial in medical patients4 and the RABBIT 2 Surgery trial5 that would make the results not completely comparable. In RABBIT 2, the medical patients included were on diet alone or any combination of oral antidiabetic agents (not on insulin), and they were started on a total daily dose of insulin of either 0.4 or 0.5 U/kg/day, depending on the glucose level. In RABBIT 2 Surgery, patients who were on insulin at home with a total daily dose of 0.4 U/kg or less were also included, and the starting daily dose of insulin was 0.5 U/kg (unless they were older or had a high serum creatinine).
In view of all the above, we agree with Drs. Ditch and Moore that if there is concern for hypoglycemia, the clinician should reduce the insulin dose in the manner that evidence from the local practice suggests, without causing undue hyperglycemia and postsurgical complications.
- Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125:1007–1021.
- King JT, Goulet JL, Perkal MF, Rosenthal RA. Glycemic control and infections in patients with diabetes undergoing noncardiac surgery. Ann Surg 2011; 253:158–165.
- Frisch A, Chandra P, Smiley D, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care 2010; 33:1783–1788.
- Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care 2007; 30:2181–2186.
- Umpierrez GE, Smiley D, Jacobs S, Peng L, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011; 34:256–261.
In Reply: We appreciate the kind words of Drs. Ditch and Moore, as well as their opinion.
Our article was intentionally brief—a 1-Minute Consult—and so could not cover all specific situations we encounter in clinical practice. We meant only to provide a general approach in this matter.
Quite often before surgery, patients receive less basal insulin than needed, or none at all, rather than too much. It has to be borne in mind that perioperative hyperglycemia—not just hypoglycemia—is linked with poor outcomes in cardiac1 and noncardiac surgery.2,3
Through our scenarios and suggestions, we have taken steps to err on the side of preventing hypoglycemia while averting hyperglycemia, at the same time making it easy to calculate the dose. In a scenario in which the basal insulin dose is about the same as the total of the prandial boluses, we have not yet seen evidence that raises concern for hypoglycemia, maybe because many of the patients with type 2 diabetes seen in our institution for surgery take, in addition to insulin, oral agents or noninsulin injections (which are appropriately withheld before surgery), and have suboptimal glycemic control on their home regimen. But if a physician has concerns for hypoglycemia, a dose reduction should be made.
There were some differences between the RABBIT 2 trial in medical patients4 and the RABBIT 2 Surgery trial5 that would make the results not completely comparable. In RABBIT 2, the medical patients included were on diet alone or any combination of oral antidiabetic agents (not on insulin), and they were started on a total daily dose of insulin of either 0.4 or 0.5 U/kg/day, depending on the glucose level. In RABBIT 2 Surgery, patients who were on insulin at home with a total daily dose of 0.4 U/kg or less were also included, and the starting daily dose of insulin was 0.5 U/kg (unless they were older or had a high serum creatinine).
In view of all the above, we agree with Drs. Ditch and Moore that if there is concern for hypoglycemia, the clinician should reduce the insulin dose in the manner that evidence from the local practice suggests, without causing undue hyperglycemia and postsurgical complications.
In Reply: We appreciate the kind words of Drs. Ditch and Moore, as well as their opinion.
Our article was intentionally brief—a 1-Minute Consult—and so could not cover all specific situations we encounter in clinical practice. We meant only to provide a general approach in this matter.
Quite often before surgery, patients receive less basal insulin than needed, or none at all, rather than too much. It has to be borne in mind that perioperative hyperglycemia—not just hypoglycemia—is linked with poor outcomes in cardiac1 and noncardiac surgery.2,3
Through our scenarios and suggestions, we have taken steps to err on the side of preventing hypoglycemia while averting hyperglycemia, at the same time making it easy to calculate the dose. In a scenario in which the basal insulin dose is about the same as the total of the prandial boluses, we have not yet seen evidence that raises concern for hypoglycemia, maybe because many of the patients with type 2 diabetes seen in our institution for surgery take, in addition to insulin, oral agents or noninsulin injections (which are appropriately withheld before surgery), and have suboptimal glycemic control on their home regimen. But if a physician has concerns for hypoglycemia, a dose reduction should be made.
There were some differences between the RABBIT 2 trial in medical patients4 and the RABBIT 2 Surgery trial5 that would make the results not completely comparable. In RABBIT 2, the medical patients included were on diet alone or any combination of oral antidiabetic agents (not on insulin), and they were started on a total daily dose of insulin of either 0.4 or 0.5 U/kg/day, depending on the glucose level. In RABBIT 2 Surgery, patients who were on insulin at home with a total daily dose of 0.4 U/kg or less were also included, and the starting daily dose of insulin was 0.5 U/kg (unless they were older or had a high serum creatinine).
In view of all the above, we agree with Drs. Ditch and Moore that if there is concern for hypoglycemia, the clinician should reduce the insulin dose in the manner that evidence from the local practice suggests, without causing undue hyperglycemia and postsurgical complications.
- Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125:1007–1021.
- King JT, Goulet JL, Perkal MF, Rosenthal RA. Glycemic control and infections in patients with diabetes undergoing noncardiac surgery. Ann Surg 2011; 253:158–165.
- Frisch A, Chandra P, Smiley D, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care 2010; 33:1783–1788.
- Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care 2007; 30:2181–2186.
- Umpierrez GE, Smiley D, Jacobs S, Peng L, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011; 34:256–261.
- Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125:1007–1021.
- King JT, Goulet JL, Perkal MF, Rosenthal RA. Glycemic control and infections in patients with diabetes undergoing noncardiac surgery. Ann Surg 2011; 253:158–165.
- Frisch A, Chandra P, Smiley D, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care 2010; 33:1783–1788.
- Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care 2007; 30:2181–2186.
- Umpierrez GE, Smiley D, Jacobs S, Peng L, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011; 34:256–261.
A comment on a CME test question
To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”
While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.
I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.
To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”
While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.
I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.
To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”
While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.
I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.
Stress ulcer prophylaxis
To the Editor: In the January 2014 issue, Eisa et al1 suggested that patients who require prolonged mechanical ventilatory support, ie, for more than 48 hours, should receive stress ulcer prophylaxis. This recommendation came from a study by Cook et al2 in 1994, which found a significant increase in the risk of gastrointestinal blood loss in this group of patients. Other studies have shown a different result. Zandstra et al3 found an extremely low rate of stress ulcer-related bleeding in this group in the absence of stress ulcer prophylaxis. Another study4 in critically ill patients also found no relationship between stress ulcer incidence and prolonged mechanical ventilatory support. Interestingly, that study found that prolonged use of a nasogastric tube is the major risk factor for developing a stress ulcer.4 The explanation for why newer studies did not demonstrate the relationship between mechanical ventilation and stress ulcer development may lie in the result of a meta-analysis by Marik et al,5 which showed that stress ulcer prophylaxis may not be required in a patient who receives early enteral nutrition. That practice was not common in the past, including at the time the original study was conducted.
According to current evidence, mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer. The medical community should start questioning the routine practice of stress ulcer prophylaxis in this group of patients. In addition, more studies have identified the adverse effects of acid-suppression therapy in this group of patients, and these effects likely make the harms outweigh the benefits. This notion was confirmed in the most recent meta-analysis by Krag et al.6 In summary, the practice of routine stress ulcer prophylaxis in all mechanically ventilated patients will likely change in the future, with more focus on patients who are at higher risk.
- Eisa N, Bazerbachi F, Alraiyes AH, Alraies MC. Do all hospitalized patients need stress ulcer prophylaxis? Cleve Clin J Med 2014; 81:23–25.
- Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377–381.
- Zandstra DF, Stoutenbeek CP. The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med 1994; 20:335–340.
- Ellison RT, Perez-Perez G, Welsh CH, et al. Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of Helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group. Crit Care Med 1996; 24:1974–1981.
- Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38:2222–2228.
- Krag M, Perner A, Wetterslev J, Wise MP, Hylander Møller M. Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med 2014; 40:11–22.
To the Editor: In the January 2014 issue, Eisa et al1 suggested that patients who require prolonged mechanical ventilatory support, ie, for more than 48 hours, should receive stress ulcer prophylaxis. This recommendation came from a study by Cook et al2 in 1994, which found a significant increase in the risk of gastrointestinal blood loss in this group of patients. Other studies have shown a different result. Zandstra et al3 found an extremely low rate of stress ulcer-related bleeding in this group in the absence of stress ulcer prophylaxis. Another study4 in critically ill patients also found no relationship between stress ulcer incidence and prolonged mechanical ventilatory support. Interestingly, that study found that prolonged use of a nasogastric tube is the major risk factor for developing a stress ulcer.4 The explanation for why newer studies did not demonstrate the relationship between mechanical ventilation and stress ulcer development may lie in the result of a meta-analysis by Marik et al,5 which showed that stress ulcer prophylaxis may not be required in a patient who receives early enteral nutrition. That practice was not common in the past, including at the time the original study was conducted.
According to current evidence, mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer. The medical community should start questioning the routine practice of stress ulcer prophylaxis in this group of patients. In addition, more studies have identified the adverse effects of acid-suppression therapy in this group of patients, and these effects likely make the harms outweigh the benefits. This notion was confirmed in the most recent meta-analysis by Krag et al.6 In summary, the practice of routine stress ulcer prophylaxis in all mechanically ventilated patients will likely change in the future, with more focus on patients who are at higher risk.
To the Editor: In the January 2014 issue, Eisa et al1 suggested that patients who require prolonged mechanical ventilatory support, ie, for more than 48 hours, should receive stress ulcer prophylaxis. This recommendation came from a study by Cook et al2 in 1994, which found a significant increase in the risk of gastrointestinal blood loss in this group of patients. Other studies have shown a different result. Zandstra et al3 found an extremely low rate of stress ulcer-related bleeding in this group in the absence of stress ulcer prophylaxis. Another study4 in critically ill patients also found no relationship between stress ulcer incidence and prolonged mechanical ventilatory support. Interestingly, that study found that prolonged use of a nasogastric tube is the major risk factor for developing a stress ulcer.4 The explanation for why newer studies did not demonstrate the relationship between mechanical ventilation and stress ulcer development may lie in the result of a meta-analysis by Marik et al,5 which showed that stress ulcer prophylaxis may not be required in a patient who receives early enteral nutrition. That practice was not common in the past, including at the time the original study was conducted.
According to current evidence, mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer. The medical community should start questioning the routine practice of stress ulcer prophylaxis in this group of patients. In addition, more studies have identified the adverse effects of acid-suppression therapy in this group of patients, and these effects likely make the harms outweigh the benefits. This notion was confirmed in the most recent meta-analysis by Krag et al.6 In summary, the practice of routine stress ulcer prophylaxis in all mechanically ventilated patients will likely change in the future, with more focus on patients who are at higher risk.
- Eisa N, Bazerbachi F, Alraiyes AH, Alraies MC. Do all hospitalized patients need stress ulcer prophylaxis? Cleve Clin J Med 2014; 81:23–25.
- Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377–381.
- Zandstra DF, Stoutenbeek CP. The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med 1994; 20:335–340.
- Ellison RT, Perez-Perez G, Welsh CH, et al. Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of Helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group. Crit Care Med 1996; 24:1974–1981.
- Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38:2222–2228.
- Krag M, Perner A, Wetterslev J, Wise MP, Hylander Møller M. Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med 2014; 40:11–22.
- Eisa N, Bazerbachi F, Alraiyes AH, Alraies MC. Do all hospitalized patients need stress ulcer prophylaxis? Cleve Clin J Med 2014; 81:23–25.
- Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377–381.
- Zandstra DF, Stoutenbeek CP. The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med 1994; 20:335–340.
- Ellison RT, Perez-Perez G, Welsh CH, et al. Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of Helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group. Crit Care Med 1996; 24:1974–1981.
- Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38:2222–2228.
- Krag M, Perner A, Wetterslev J, Wise MP, Hylander Møller M. Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med 2014; 40:11–22.
In reply: Stress ulcer prophylaxis
In Reply: We welcome the comments from Dr. Chongnarungsin on our article and the opportunity to further discuss our opinions.
In our paper, we discussed current recommendations for prophylaxis of stress ulcer-related bleeding in hospitalized patients and advocated against the blind administration of drugs without risk stratification.
The landmark trial that provides the most-cited definitions and the risk factors for clinically significant stress ulcer-related bleeding in critically ill patients was published in 1994 by Cook et al.1 In their multicenter prospective cohort study of 2,252 patients, the authors reported that prolonged mechanical ventilation is an important risk factor for clinically significant stress ulcer-related bleeding.
Another major prospective cohort study observed an incidence rate of clinically significant stress ulcer-related bleeding of 3.5%.2
Dr. Chongnarungsin cites another prospective cohort study of 183 patients from the same era,3 wherein the authors defined stress ulcer-related bleeding as bleeding requiring transfusion of packed red blood cells, found on endoscopy or on postmortem evaluation. This was in contrast to the 1994 study of Cook et al,1 who had a more rigorous and comprehensive definition for overt and clinically significant stress ulcer-related bleeding, applied by up to three independent adjudicators not involved in the patients’ care. Their definition not only entailed a more accurate transfusion-dependent bleeding criterion, but also included hemodynamic and laboratory criteria. As such, the “very low rate” of stress ulcer-related bleeding reported by Zandstra et al3 should be critically appraised. Of note, the authors in that study did not report the rates of patients who received early enteral feeding, and their patients received cefotaxime for digestive tract decontamination, an important confounder to the interpretation of the study results.
Indeed, the remarkable variation in estimates of the incidence of stress ulcer-related bleeding is probably related to the lack of a uniform definition. Even when rates of endoscopic and occult bleeding are set aside, agreement is lacking as to which category of bleeding is clinically significant.
Dr. Chongnarungsin also cites the study by Ellison et al4 of a cohort of 874 patients who had no previous gastrointestinal bleeding or peptic ulcer disease and who were enrolled in a multicenter randomized controlled trial of prophylactic intravenous immune globulin to prevent infections associated with an intensive care unit. In a secondary objective, the authors did not identify coagulopathy or prolonged mechanical ventilation as a principal risk factor for bleeding. The authors ascribed this discrepancy with previously published literature to their unique study population, which consisted predominantly of elderly men and rarely included trauma patients. In light of these unique peculiarities of their population, the lack of an association between prolonged mechanical ventilation and stress ulcer-related bleeding cannot be determined. Moreover, that study showed that prolonged nasogastric tube insertion was one of the risk factors for increased risk of gastrointestinal bleeding, and not the risk factor for development of stress ulcer as stated by Dr. Chongnarungsin.
The decrease in the incidence of stress ulcer-related bleeding in critically ill patients over the years could be attributed to an era effect, from advances in critical care medicine and prophylactic methods.5 We agree with Dr. Chongnarungsin that the increased introduction of early enteral feeding may have also contributed to the reduced incidence of stress ulcer-related bleeding.6 However, we think the conclusion that “mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer” is overelaborated, and we believe that strong evidence demonstrates this association.1,2
Alternatively, we recognize the lack of mortality-benefit evidence for stress ulcer prophylaxis. This notwithstanding, according to recent Surviving Sepsis Campaign guidelines, the use of stress ulcer prophylaxis is listed as a 1B recommendation (strong recommendation) for severely septic patients who require prolonged mechanical ventilation. In addition, the updated 2014 guidelines of the American Society of Health-System Pharmacists7 continue to recommend stress ulcer prophylaxis in the context of mechanical ventilation, with H2 receptor antagonists being the preferred first-line agents.8
It is important to acknowledge that these recommendations were endorsed despite the lack of obvious mortality benefit, and it is our opinion that large randomized controlled studies are needed to evaluate the risks and mortality benefit of these prophylaxis methods.
- Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377–381.
- Cook DJ, Griffith LE, Walter SD, et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care 2001; 5:368–375.
- Zandstra DF, Stoutenbeek CP. The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med 1994; 20:335–340.
- Ellison RT, Perez-Perez G, Welsh CH, et al. Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of Helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group. Crit Care Med 1996; 24:1974–1981.
- Duerksen DR. Stress-related mucosal disease in critically ill patients. Best Pract Res Clin Gastroenterol 2003; 17:327–344.
- Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38:2222–2228.
- Cohen H, editor. Stop stressing out: the new stress ulcer prophylaxis (SUP) guidelines are finally here! ASHP Midyear Clinical Meeting; 2013 11 Dec 2013; Orlando, FL.
In Reply: We welcome the comments from Dr. Chongnarungsin on our article and the opportunity to further discuss our opinions.
In our paper, we discussed current recommendations for prophylaxis of stress ulcer-related bleeding in hospitalized patients and advocated against the blind administration of drugs without risk stratification.
The landmark trial that provides the most-cited definitions and the risk factors for clinically significant stress ulcer-related bleeding in critically ill patients was published in 1994 by Cook et al.1 In their multicenter prospective cohort study of 2,252 patients, the authors reported that prolonged mechanical ventilation is an important risk factor for clinically significant stress ulcer-related bleeding.
Another major prospective cohort study observed an incidence rate of clinically significant stress ulcer-related bleeding of 3.5%.2
Dr. Chongnarungsin cites another prospective cohort study of 183 patients from the same era,3 wherein the authors defined stress ulcer-related bleeding as bleeding requiring transfusion of packed red blood cells, found on endoscopy or on postmortem evaluation. This was in contrast to the 1994 study of Cook et al,1 who had a more rigorous and comprehensive definition for overt and clinically significant stress ulcer-related bleeding, applied by up to three independent adjudicators not involved in the patients’ care. Their definition not only entailed a more accurate transfusion-dependent bleeding criterion, but also included hemodynamic and laboratory criteria. As such, the “very low rate” of stress ulcer-related bleeding reported by Zandstra et al3 should be critically appraised. Of note, the authors in that study did not report the rates of patients who received early enteral feeding, and their patients received cefotaxime for digestive tract decontamination, an important confounder to the interpretation of the study results.
Indeed, the remarkable variation in estimates of the incidence of stress ulcer-related bleeding is probably related to the lack of a uniform definition. Even when rates of endoscopic and occult bleeding are set aside, agreement is lacking as to which category of bleeding is clinically significant.
Dr. Chongnarungsin also cites the study by Ellison et al4 of a cohort of 874 patients who had no previous gastrointestinal bleeding or peptic ulcer disease and who were enrolled in a multicenter randomized controlled trial of prophylactic intravenous immune globulin to prevent infections associated with an intensive care unit. In a secondary objective, the authors did not identify coagulopathy or prolonged mechanical ventilation as a principal risk factor for bleeding. The authors ascribed this discrepancy with previously published literature to their unique study population, which consisted predominantly of elderly men and rarely included trauma patients. In light of these unique peculiarities of their population, the lack of an association between prolonged mechanical ventilation and stress ulcer-related bleeding cannot be determined. Moreover, that study showed that prolonged nasogastric tube insertion was one of the risk factors for increased risk of gastrointestinal bleeding, and not the risk factor for development of stress ulcer as stated by Dr. Chongnarungsin.
The decrease in the incidence of stress ulcer-related bleeding in critically ill patients over the years could be attributed to an era effect, from advances in critical care medicine and prophylactic methods.5 We agree with Dr. Chongnarungsin that the increased introduction of early enteral feeding may have also contributed to the reduced incidence of stress ulcer-related bleeding.6 However, we think the conclusion that “mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer” is overelaborated, and we believe that strong evidence demonstrates this association.1,2
Alternatively, we recognize the lack of mortality-benefit evidence for stress ulcer prophylaxis. This notwithstanding, according to recent Surviving Sepsis Campaign guidelines, the use of stress ulcer prophylaxis is listed as a 1B recommendation (strong recommendation) for severely septic patients who require prolonged mechanical ventilation. In addition, the updated 2014 guidelines of the American Society of Health-System Pharmacists7 continue to recommend stress ulcer prophylaxis in the context of mechanical ventilation, with H2 receptor antagonists being the preferred first-line agents.8
It is important to acknowledge that these recommendations were endorsed despite the lack of obvious mortality benefit, and it is our opinion that large randomized controlled studies are needed to evaluate the risks and mortality benefit of these prophylaxis methods.
In Reply: We welcome the comments from Dr. Chongnarungsin on our article and the opportunity to further discuss our opinions.
In our paper, we discussed current recommendations for prophylaxis of stress ulcer-related bleeding in hospitalized patients and advocated against the blind administration of drugs without risk stratification.
The landmark trial that provides the most-cited definitions and the risk factors for clinically significant stress ulcer-related bleeding in critically ill patients was published in 1994 by Cook et al.1 In their multicenter prospective cohort study of 2,252 patients, the authors reported that prolonged mechanical ventilation is an important risk factor for clinically significant stress ulcer-related bleeding.
Another major prospective cohort study observed an incidence rate of clinically significant stress ulcer-related bleeding of 3.5%.2
Dr. Chongnarungsin cites another prospective cohort study of 183 patients from the same era,3 wherein the authors defined stress ulcer-related bleeding as bleeding requiring transfusion of packed red blood cells, found on endoscopy or on postmortem evaluation. This was in contrast to the 1994 study of Cook et al,1 who had a more rigorous and comprehensive definition for overt and clinically significant stress ulcer-related bleeding, applied by up to three independent adjudicators not involved in the patients’ care. Their definition not only entailed a more accurate transfusion-dependent bleeding criterion, but also included hemodynamic and laboratory criteria. As such, the “very low rate” of stress ulcer-related bleeding reported by Zandstra et al3 should be critically appraised. Of note, the authors in that study did not report the rates of patients who received early enteral feeding, and their patients received cefotaxime for digestive tract decontamination, an important confounder to the interpretation of the study results.
Indeed, the remarkable variation in estimates of the incidence of stress ulcer-related bleeding is probably related to the lack of a uniform definition. Even when rates of endoscopic and occult bleeding are set aside, agreement is lacking as to which category of bleeding is clinically significant.
Dr. Chongnarungsin also cites the study by Ellison et al4 of a cohort of 874 patients who had no previous gastrointestinal bleeding or peptic ulcer disease and who were enrolled in a multicenter randomized controlled trial of prophylactic intravenous immune globulin to prevent infections associated with an intensive care unit. In a secondary objective, the authors did not identify coagulopathy or prolonged mechanical ventilation as a principal risk factor for bleeding. The authors ascribed this discrepancy with previously published literature to their unique study population, which consisted predominantly of elderly men and rarely included trauma patients. In light of these unique peculiarities of their population, the lack of an association between prolonged mechanical ventilation and stress ulcer-related bleeding cannot be determined. Moreover, that study showed that prolonged nasogastric tube insertion was one of the risk factors for increased risk of gastrointestinal bleeding, and not the risk factor for development of stress ulcer as stated by Dr. Chongnarungsin.
The decrease in the incidence of stress ulcer-related bleeding in critically ill patients over the years could be attributed to an era effect, from advances in critical care medicine and prophylactic methods.5 We agree with Dr. Chongnarungsin that the increased introduction of early enteral feeding may have also contributed to the reduced incidence of stress ulcer-related bleeding.6 However, we think the conclusion that “mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer” is overelaborated, and we believe that strong evidence demonstrates this association.1,2
Alternatively, we recognize the lack of mortality-benefit evidence for stress ulcer prophylaxis. This notwithstanding, according to recent Surviving Sepsis Campaign guidelines, the use of stress ulcer prophylaxis is listed as a 1B recommendation (strong recommendation) for severely septic patients who require prolonged mechanical ventilation. In addition, the updated 2014 guidelines of the American Society of Health-System Pharmacists7 continue to recommend stress ulcer prophylaxis in the context of mechanical ventilation, with H2 receptor antagonists being the preferred first-line agents.8
It is important to acknowledge that these recommendations were endorsed despite the lack of obvious mortality benefit, and it is our opinion that large randomized controlled studies are needed to evaluate the risks and mortality benefit of these prophylaxis methods.
- Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377–381.
- Cook DJ, Griffith LE, Walter SD, et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care 2001; 5:368–375.
- Zandstra DF, Stoutenbeek CP. The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med 1994; 20:335–340.
- Ellison RT, Perez-Perez G, Welsh CH, et al. Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of Helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group. Crit Care Med 1996; 24:1974–1981.
- Duerksen DR. Stress-related mucosal disease in critically ill patients. Best Pract Res Clin Gastroenterol 2003; 17:327–344.
- Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38:2222–2228.
- Cohen H, editor. Stop stressing out: the new stress ulcer prophylaxis (SUP) guidelines are finally here! ASHP Midyear Clinical Meeting; 2013 11 Dec 2013; Orlando, FL.
- Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377–381.
- Cook DJ, Griffith LE, Walter SD, et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care 2001; 5:368–375.
- Zandstra DF, Stoutenbeek CP. The virtual absence of stress-ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med 1994; 20:335–340.
- Ellison RT, Perez-Perez G, Welsh CH, et al. Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of Helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group. Crit Care Med 1996; 24:1974–1981.
- Duerksen DR. Stress-related mucosal disease in critically ill patients. Best Pract Res Clin Gastroenterol 2003; 17:327–344.
- Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38:2222–2228.
- Cohen H, editor. Stop stressing out: the new stress ulcer prophylaxis (SUP) guidelines are finally here! ASHP Midyear Clinical Meeting; 2013 11 Dec 2013; Orlando, FL.