With respect to the type of surgery, revision procedures generally were associated with a greater risk of infection than primary procedures (Fig. 5). On the day of surgery, patients who had revision procedures (median, 166.89; IQR, 42.17; n = 31) had significantly higher glucose levels than those who underwent primary surgery (median, 148.57; IQR, 31.20; n = 270) (p < 0.001).
When diabetic patients were compared with normal and prediabetic patients, the natural log of the glucose levels on the day of surgery was analyzed because of the large variation of glucose values in the diabetic group (Fig. 6). These groups were compared with use of t tests, which indicated that diabetic patients had significantly higher log mean glucose levels (mean and standard deviation, 5.257 ± 0.237; n = 37) when compared with normal patients (4.967 ± 0.137; n = 78) and prediabetic patients (4.985 ± 0.178; n = 105) (p < 0.001 for both comparisons). These results are not surprising; however, when the change in glucose from preoperatively to the day of surgery was evaluated with use of the t test, there were no significant differences between diabetic patients (49.96 ± 51.37; n = 34) and normal patients (49.48 ± 25.03; n = 67) or between prediabetic patients (43.88 ± 26.21; n = 100) and normal patients (p > 0.31 for both comparisons).
Finally, the relationship between age and glucose level on the day of surgery was examined with use of linear regression. Glucose levels were transformed with use of the natural log to satisfy the assumptions of this model, and younger age was almost significant (p = 0.063). On the basis of the results of this model, for every year increase in age, the natural log of the glucose level decreased by 0.00198. Therefore, there was a trend for younger patients to have higher glucose levels after surgery, but this finding did not reach significance.
There were no periprosthetic joint infections in this study population. Twenty-five patients (8.3%) had a single episode of hypoglycemia with a glucose level of <70 mg/dL, including 4 patients (1.3%) with a glucose level of <50 mg/dL. This rate of hypoglycemia compares favorably with that in the Rabbit-2 study, in which hypoglycemia occurred in 21% of patients23. This improvement is attributed to the stop-insulin trigger that was added to the protocol. Female patients tend to become hypoglycemic more often than male patients. There were no injuries related to these hypoglycemic episodes. Complications included 5 falls, all of which were related to use of femoral nerve blocks. One of the 5 patients who fell while in the hospital was returned to the operating room for irrigation and reclosure of a traumatic wound dehiscence.
One patient in the treatment group died as the result of a cerebrovascular accident while in the hospital. She did not have a blood glucose level of <70 mg/dL, so the death was not related to any hypoglycemic event (Table I).
The present study demonstrates that a standardized protocol involving the use of subcutaneous insulin for the treatment of postoperative stress-induced hyperglycemia was both safe to use on an orthopaedic ward and effective for the correction of hyperglycemia in both diabetic and nondiabetic patients. The components of the protocol, including standard order sets for the use of basal-bolus subcutaneous insulin and point-of-care glucose monitors, are commonly available in most hospitals.
The barriers to the use of the insulin protocol have been a reluctance to use insulin from a safety standpoint (that is, a fear of the effects of hypoglycemia) and the lack of realization, until recently, that nondiabetic patients also are at risk for hyperglycemia-related periprosthetic joint infection3. The findings of the present study showed that hyperglycemia in nondiabetic patients responded to treatment with insulin in a predictable manner and that the stress-induced phenomenon generally subsided spontaneously within 48 hours, allowing for the discontinuation of insulin before the time of discharge. Although discontinuation of the insulin protocol at a threshold of 100 mg/dL is supported in the literature26, the stop trigger has now been changed to 110 mg/dL on the basis of the experience in the present study. This change, along with strict hypoglycemia guidelines, has led to increased safety. Diabetic patients respond more erratically (i.e., they have increased glycemic variability) and tend to have a slower decrease in hyperglycemia, occasionally requiring a longer time on the protocol. For a patient with a history of particularly poor glycemic control, a preoperative consultation with an endocrinologist would be in order.
The reason for the increased risk of infection in nondiabetic as compared with diabetic patients for a given level of hyperglycemia is not well understood; however, it appears to be related to an adjustment by the immune system of diabetic patients to chronic glycemic swings. The immune system of nondiabetic patients, on the other hand, appears to shut down in response to the unaccustomed hyperglycemia.
The primary limitation of the present study is that it was a retrospective cohort study involving a relatively small patient population. The absence of periprosthetic joint infection during this study is suggestive of efficacy against infection (with a national average incidence of approximately 0.5% to 1.5% for patients undergoing primary total joint replacement and at least double that for those undergoing revision total joint replacement7,18); however, because of the lack of a control group, the efficacy cannot be considered to have been proven.
The first strength of the present study is that it was based on the largest and most complete collection of postoperative glycemic data on patients with total hip and total knee replacements that we are aware of in the literature, with >4,000 point-of-care glucose levels for the 301 patients. Statistical analysis revealed correspondence of these data with known risk factors for infection already in the literature, including male sex10-13, morbid obesity 4,11,15-17, revision surgery7,8, and diabetes3-5. A trend toward hyperglycemia was noted in younger patients, which also been cited as a risk factor14,15. It is important to understand that the data do not represent the natural history of the stress-related glycemic response beyond the day of surgery but instead show the response to treatment, with all treatment groups responding in a salutary manner to the use of insulin. To understand the natural history of the glycemic stress response in patients undergoing total joint replacement, it is necessary to evaluate the work of Maeda et al.27, who closely collected glycemic data but did not manage their patients with insulin. In their study of 236 patients who had undergone total joint replacement, Maeda et al. demonstrated a persistence of hyperglycemia through the first 2 days postoperatively, with peak glucose levels occurring in the afternoon of the second day. All 3 of the infections in that study occurred in patients each of whom had an average glucose level of >200 mg/dL, regardless of their diabetic status.
The second strength of the present study is its unique approach to the problem of periprosthetic joint infection caused by hyperglycemia. Despite the widespread use of insulin protocols in other surgical disciplines such as open-heart surgery, general surgery, and colorectal surgery, there has been no apparent previous standardized use, especially for nondiabetic patients, in total joint surgery. While most authors in the field of orthopaedic surgery have focused on the preoperative evaluation of diabetes and hyperglycemia, the protocol described in the present study takes direct aim at the source of the risk: postoperative stress-induced hyperglycemia.
The use of this protocol requires cooperation on the part of the pharmacy, laboratory, hospitalists, and especially nursing staff for its safe and effective execution. The protocol can be safely managed on the orthopaedic ward without the need for monitoring in the ICU. Patients should be prepared for the possibility that if postoperative hyperglycemia is identified, a 2-day stay in the acute-care setting may be necessary.
The successful use of a standardized postoperative insulin protocol in the present study should encourage orthopaedists to join surgeons in other disciplines, not only those involved in total joint surgery but also those involved in other areas such as spine surgery and major trauma surgery, in treating the risks of postoperative hyperglycemia. A larger randomized, controlled study (similar to the Rabbit-2 study in general surgery) to test the efficacy against periprosthetic joint infection is warranted.
Investigation performed at the Department of Orthopaedic Surgery, Mercy Health System, Cincinnati, Ohio
Disclosure: Funding through Mercy Health Administration. No external funding was received. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A4).
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