key: cord-0766131-16o2rqk5
authors: Asiri, Alanood A.; Alguwaihes, Abdullah M.; Jammah, Anwar A.; Alfadda, Assim A.; Al-Sofiani, Mohammed E.
title: Assessment of the Effectiveness of a Protocol to Manage Dexamethasone-induced Hyperglycemia among Hospitalized Patients with COVID-19
date: 2021-08-03
journal: Endocr Pract
DOI: 10.1016/j.eprac.2021.07.016
sha: 137ae001eb376e0ecae4d725036aec9fa6b4c145
doc_id: 766131
cord_uid: 16o2rqk5

BACKGROUND: Well-controlled glucose (i.e. 70-180 mg/dl) has been associated with lower mortality from COVID-19. The addition of dexamethasone to COVID-19 treatment protocols has raised concerns about the potential negative consequences of dexamethasone-induced hyperglycemia. METHODS: We developed a protocol to guide the management of dexamethasone-induced hyperglycemia in hospitalized patients with COVID-19. Two of the four medical teams managing patients with COVID-19 at a tertiary center used the protocol and the other two teams continued to manage hyperglycemia at the discretion of the treating physicians (“Protocol” and “Control” groups, respectively). The glycemic control and clinical outcomes in 163 patients hospitalized with COVID-19 and dexamethasone-induced hyperglycemia between July 5th and September 30th, 2020 were retrospectively reviewed and compared between the two groups. RESULTS: Compared to the “Control” group, the “Protocol” group had higher proportions of patients with well-controlled glucose across all pre-meals and bedtime glucose readings throughout the hospitalization. The differences in glycemic control between the two groups were statistically significant for fasting glucose on days 4, 5, and discharge day; pre-lunch glucose on discharge day; pre-dinner glucose on days 3, 5, and discharge day; and bedtime glucose on day 1 (all p<0.05). After adjusting for age, sex, nationality, BMI, Charlson score, and diabetes status; patients in the “Protocol” group were more likely to have well-controlled glucose compared to those in the “Control” group. Moreover, the in-hospital mortality was significantly lower in the “Protocol” group compared to the “Control” group (12.93 and 29.93%, respectively, p=0.01) CONCLUSIONS: The implementation of a protocol to manage dexamethasone-induced hyperglycemia in hospitalized patients with COVID-19 resulted in more patients achieving well-controlled glucose levels and was associated with lower mortality of COVID-19.

The implementation of a protocol to manage dexamethasone-induced hyperglycemia in hospitalized patients with COVID-19 resulted in more patients achieving well-controlled glucose levels and was associated with lower mortality of COVID-19.

Keywords: Hyperglycemia, Dexamethasone, COVID-19, Diabetes Mellitus, Protocol.

The global pandemic of the novel coronavirus COVID-2019 has placed a major burden on health care systems worldwide. The first case of COVID-19 in Saudi Arabia was reported in March 2020. As of this moment, numbers of confirmed cases in Saudi Arabia has surpassed 395,000 cases including more than 6,700 deaths. 1 Factors associated with worse outcomes of COVID-19 include older age and the presence of underlying chronic diseases such as diabetes, hypertension, obesity, and chronic respiratory diseases. 2 Several studies hallmark diabetes and hyperglycemia as important risk factors of morbidity and mortality of COVID-19. [3] [4] [5] [6] [7] [8] Moreover, early-onset hyperglycemia and hyperglycemia on presentation to the hospital has been associated with increased mortality of COVID-19 in people with and without diabetes . 9, 10 After the promising results of the RECOVERY trial, dexamethasone emerged as a promising treatment of COVID-19 with a significant reduction in mortality in hospitalized patients with hypoxemia. 11 The dexamethasone dose used in the trial was 6 mg daily for 10 days, a dose approximately six to eight times the physiological equivalent of glucocorticoid production and is associated with a high risk of steroid-induced hyperglycemia and other metabolic sequelae in people with and without diabetes. 12 This, along with the deleterious effect of COVID-19 on insulin sensitivity and beta cell function as a result of the cytokine J o u r n a l P r e -p r o o f storm, can lead to severe hyperglycemia and subsequently may instigate acute glycemic complications such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. [13] [14] [15] [16] [17] Hyperglycemia on hospital admission as well as during the first few days of admission has been linked to severe illness and death among patients with COVID-19 [8] [9] 18 . A study conducted in Wuhan, China showed a reduced mortality in patients admitted with COVID-19 who had glucose values between 70 to180 mg/dl throughout the hospital stay compared to those who had glucose levels >180 mg/dl. 18 Achieving glucose targets when managing hospitalized patients with COVID-19 has been a challenging task during the pandemic for several reasons. The shortage of staff and personal protective equipment, along with the need to minimize staff exposure during the outbreak have hindered glycemic control in patients with COVID-19. In addition, health care providers from various specialties, including those who may not be very familiar with glucose management and steroid-induced hyperglycemia, have been called to manage patients with COVID-19. As a result, many patients with COVID-19 had inadequate glycemic control during their hospital stay, particularly after the addition of dexamethasone to the treatment protocols of severe COVID-19. 19 In many instances, these patients could have benefited from a more aggressive glucose management to maintain glucose levels between 70 and 180 mg/dl.

Here, we present a simplified, yet comprehensive, protocol to guide the management of dexamethasone-induced hyperglycemia in hospitalized patients with COVID-19. We also evaluate the clinical effectiveness of this protocol in managing dexamethasone-induced hyperglycemia in the real world during the peak of COVID-19 cases in a tertiary center in Saudi Arabia.

J o u r n a l P r e -p r o o f

The study was conducted at one of the tertiary centers in Saudi Arabia that were designated to manage patients with COVID-19 during the pandemic. We developed a protocol on how to manage dexamethasone-induced hyperglycemia as a Quality Improvement Project that was approved by the Institutional Review Board at the tertiary center ( Figure 1 ). The protocol was disseminated to two of the four medical teams that were managing hospitalized patients with COVID-19 in the non-ICU setting between July 5th and September 30th, 2020. We retrospectively reviewed the electronic medical records and glucose values of all adult patients with COVID-19 who were treated with dexamethasone as part of the COVID-19 treatment protocol and were managed by one of the four medical teams at our hospital during the study period. Of these patients, we excluded those who had no diabetes and maintained glucose values <180 mg/dl throughout the hospitalization, as well as those who required IV insulin infusion within the first three days of hospitalization. We included only patients with COVID-19 who were treated with dexamethasone and had any of the following: a) known history of diabetes, b) previously undiagnosed diabetes (defined as having an A1C ≥6.5 on admission), and c) no diabetes but developed hyperglycemia after the initiation of dexamethasone (defined as ≥1 glucose value above 180 mg/dl). In this study, we refer to all three groups as patients with dexamethasone-induced hyperglycemia.

The protocol guides healthcare professionals through all the steps needed to manage The protocol also guides healthcare professionals through the daily assessment of glycemic patterns and how to titrate basal, nutritional, and correctional insulin doses accordingly. The last section of the protocol provides general guidelines for a safe discharge process to avoid hypoglycemia after the discontinuation of dexamethasone and ensure a close follow up plan ( Figure 1 ). 20

The "Protocol" group included patients admitted under the care of the two medical teams that had received and implemented the protocol for the management of dexamethasone-induced hyperglycemia; whereas the "Control" group included patients admitted under the care of the other two medical teams that had not received nor implemented the protocol. Dexamethasone-induced hyperglycemia in the latter group was managed according to the usual care and at the discretion of the treating physicians. The four COVID-19 medical teams at our institution were comparable in the number and level of training of their members as well as the acuity of patients admitted to each team. They were run by medical specialists only; and each team consisted of a medical attending, a senior medical resident or registrar, and three junior medical residents. The senior medical residents J o u r n a l P r e -p r o o f and registrars were responsible for the protocol implementation in the two teams assigned to use the protocol. The other two medical teams continued to manage dexamethasone-induced hyperglycemia according to the usual care at the discretion of the treating physicians and without using the protocol.

We collected data from the electronic medical records including age; sex; nationality; BMI; vital signs; comorbidities (diabetes, hypertension, dyslipidemia, chronic lung disease, chronic kidney disease, ischemic heart disease, and heart failure); calculated Charlson, quick sequential organ failure assessment (qSOFA), CURB-65 scores; clinical outcomes (including rates of in-hospital mortality, length of hospital stay, need for invasive and non-invasive ventilation, need for IV insulin infusion, and rates of 30-day and 6-month hospital readmission); and point-of-care glucose values (pre-meals and bedtime) during the first five days of hospitalization, as well as on day of discharge for those hospitalized for longer than 5 days. Well-controlled glucose was defined as having point-of-care glucose values between 70 and 180 mg/dl throughout the day. 8, 18 Mild hypoglycemia was defined as a glucose level between 54 and 70 mg/dl, whereas severe hypoglycemia was defined as a glucose level of ≤54 mg/dl).

All significance testing was 2-tailed with α of 0.05, and data were analyzed using Stata Statistical Software (release 15). Variables distributions were examined for normality using the Shapiro-Wild test and visual examination of histograms. The non-normally distributed variables of BMI, maximum temperature, respiratory rate, and Charlson score J o u r n a l P r e -p r o o f were presented as medians and interquartile ranges (IQR). Baseline characteristics and differences in glycemic control measures and clinical outcomes were compared by use of protocol using t-test for continuous and normally distributed data, Kruskal-Wallis test for continuous and non-normally distributed data, and chi-squared tests of homogeneity for categorical variables. Logistic regression analysis was used to examine the association between the use of protocol and achieving well-controlled glucose in patients with dexamethasone-induced hyperglycemia before and after adjusting for age, sex, nationality, BMI, Charlson score, and diabetes status.

The study included 163 subjects with COVID-19 and dexamethasone-induced hyperglycemia, of whom 116 were managed using the protocol "Protocol" group and 47 were managed without using the protocol at the discretion of the treating physician "Control" group. On admission, there were no significant differences in age, sex, BMI, prevalence of diabetes, nationality, and qSOFA, CURB-65, and Charlson score between the "Protocol" and "Control" groups (all p>0.05) ( Table 1) .

Fasting, pre-lunch, pre-dinner, and bedtime point-of-care glucose readings were compared between the "Control" and "Protocol" groups throughout the first five days of admission and on day of discharge. Fasting glucose readings on the first day were discarded, as it was unknown if the patients were fasting at time of admission or not. The "Protocol" group had significantly lower fasting glucose levels than the "Control" group on day 3 mg/dL, respectively, p <0.01). Pre-lunch glucose levels were also significantly lower in the "Protocol" group than those in the "Control" group on day 4 (183.6 vs 243 mg/dL, respectively, p<0.05), day 5 (162 vs 212.4 mg/dL, respectively, p<0.05), and day of discharge (145.8 vs 246.6 mg/dL, respectively, p<0.01). Similarly, pre-dinner glucose values on day 3 and day 5 and bedtime glucose on day 1 were all significantly lower in those managed using the protocol versus those who were not (all p <0.05) ( Table 2 ).

Study participants in the "Protocol" group were more likely to have well-controlled glucose (i.e. 70-180 mg/dL) across all pre-meal and bedtime values and throughout the study period compared to those in the "Control" group. These differences were statistically significant for fasting glucose on days 4, 5, and day of discharge; pre-Lunch glucose on day of discharge, pre-Dinner glucose on days 3, 5, and day of discharge; and bedtime glucose on day 1. (all p-values <0.05) (Figure 2) . A sensitivity analysis showed no major differences in the performance of the protocol among people with versus without diabetes (data not shown).

The "Protocol" group had a significantly lower in-hospital mortality than the "Control" group (12.93 vs 29.93%, respectively, p=0.01). Moreover, patients in the "Protocol" group were less likely to require ICU admission, IV insulin infusion, or mechanical ventilation compared to those in the "Control" group, although none of these differences were statistically significant. Likewise, there were no statistically significant differences in the numbers of patients who developed one or more events of mild or severe inpatient hypoglycemia between the "Protocol" and the "Control" groups, although a slightly J o u r n a l P r e -p r o o f higher number of patients in the "Protocol" group developed hypoglycemia during the first 5 days of hospitalization (i.e. insulin titration period) and a slightly higher number of patients in the "Control" group developed hypolgylcemia after day 5 of hospitalization (Table 3) .

The results of univariate and multivariate logistic regression analyses examining the relationship between the use of inpatient management protocol of dexamethasone-induced hyperglycemia and having a well-controlled glucose level (i.e. 70-180 mg/dl) among patients with COVID-19 are shown in Table 3 . Compared to participants in the Control group, those who were managed using the protocol were two to four times as likely to have well- 1.89, 19.18) ; respectively). Similarly, patients managed using the protocol were more likely to have pre-dinner and bedtime glucose readings within target throughout the study period compared to those managed without using the protocol (Table 3) .

J o u r n a l P r e -p r o o f Our study highlights the clinical effectiveness of a simple, yet comprehensive, protocol developed during the peak of COVID-19 cases in Saudi Arabia to guide the management of dexamethasone-induced hyperglycemia among hospitalized patients with severe COVID-19. Patients who were managed using this protocol were more likely to attain glucose values between 70 and 180 mg/dl throughout the hospital stay; a glucose range that has been previously linked to lower mortality of COVID-19 among hospitalized patients. 18 The most prominent improvement in glucose control with the use of our protocol was noted in the fasting and pre-dinner glucose levels. This is likely explained by the relatively early initiation of basal insulin in the "Protocol" group, as recommended by our protocol, compared to standard practice. In addition, dexamethasone exerts its peak effect on glucose levels approximately 9 to 12 hours after the dose administration. 21,22 As our facility's practice is to administer most medications, including dexamethasone, at around 9 AM, the effect of dexamethasone on glucose control appears to have peaked around the pre-dinner time (i.e. approximately 6 PM). This is evident in the "Control" group that had a progressive worsening of glucose control throughout the hospital stay, particularly at the pre-dinner time.

On the contrary, the "Protocol" group had a continuous improvement in glucose control throughout the hospital stay, including at pre-dinner time.

The association between hyperglycemia on admission, as well as during the hospital stay, and poor outcomes of COVID-19 and mortality has been shown in multiple studies. [3] [4] [5] [6] [7] [8] [9] [10] In our study, patients who were managed using the protocol had a significantly lower inhospital mortality compared to those managed using the standard practice. Moreover, the "Protocol" group had a trend toward a lower risk of ICU admission, initiation of IV insulin infusion, and need for mechanical ventilation. Whether hyperglycemia is an independent predictor of severe COVID-19 and mortality or is simply a marker of severe illness in To account for the severity of chronic medical conditions on admission as a potential confounder, we adjusted for the Charlson score in the model examining the association between the use of protocol and achieving well-controlled glucose and the findings remained the same. Our protocol is designed to improve the patients' glycemic control without compromising the patients' nor the health care providers' safety. It is designed to improve the patients' glucose control without significantly increasing the risk of insulin-induced hypoglycemia. As we were developing the protocol, we took into consideration the staff shortages, need to minimize nurses exposure to patients with COVID-19, and the fact that patients with COVID-19 were less frequently checked upon due to the low nurse-to-patient ratios during the pandemic. Minimizing the risk of hypoglycemia was a priority in our protocol, particularly when managing patients who are unable to express symptoms of hypoglycemia due to severe respiratory illness, altered mental status, sedation, or other factors. Therefore, we recommend a relatively low dose of 0.1 unit/kg/day as the starting dose of basal insulin with a gradual titration based on glucose values afterward. The J o u r n a l P r e -p r o o f conservative nature of the protocol may explain why it took two days for the differences in glucose levels between the "Protocol" and "Control" groups to become statistically significant. For a more rapid improvement in glycemic control, it might be reasonable to start with a basal insulin dose of 0.2 unit/kg/day in patients who are deemed low risk of hypoglycemia.

To the best of our knowledge, this is the first study to examine the effectiveness of a steroid-induced hyperglycemia management protocol among hospitalized patients with COVID-19. The strengths of our study include the simplicity and comprehensiveness of our protocol which makes it easy to implement and more likely to adhere to in most healthcare facilities that care for people with COVID-19 and steroid-induced hyperglycemia. Our findings have clinical implications during ordinary times and times of disasters when shortage of staff is a major limiting factor to achieving inpatient target glucose levels.

Moreover, we were able to assess the severity of COVID-19 in our study participants using the Charlson score, a comorbidity index that predicts the 10-year survival in patients with multiple comorbidities, and adjust for any potential confounding effect of illness severity on the association between use of protocol and glycemic control. Our findings are limited to patients admitted to the non-ICU medical setting. This, along with the fact that the study was carried out in a single tertiary center in Saudi Arabia, limit the generalizability of our findings. The retrospective nature of our analysis may have resulted in a selection bias with "healthier" patients being more likely to be managed by their physicians using our protocol; however, this seems to have not been the case as both study groups had comparable qSOFA scores and other markers of disease severity at baseline. Moreover, the limited number of point-of-care (POC) glucose readings at certain time-points may have contributed to the lack of significant differences in glycemic control between the "Protocol" and "Control" groups at J o u r n a l P r e -p r o o f those time-points. This can be addressed with the use of continuous glucose monitors (CGMs) in the inpatient setting in future studies. In addition, our hospital has no standardized protocols for the inpatient management of diabetes which may have negatively impacted the glycemic control in the "Control" group. Finally, we do not have data to confirm that the use of our protocol resulted in less exposure of staff to patients with COVID-19. However, we believe that it did so through offering the option of two POC glucose checks per day when appropriate, minimizing the risk of frequent hyper-and/or hypoglycemia that often prompt a glucose check with or without the administration of correctional insulin or dextrose; and minimizing the rates of IV insulin initiation to manage hyperglycemia in the "Protocol" group.

In conclusion, the implementation of a simplified protocol for the management of dexamethasone-induced hyperglycemia in hospitalized patients with COVID-19 resulted in a better glycemic control and was associated with better clinical outcomes and lower mortality of COVID-19. Future randomized-controlled studies are needed to compare the inpatient glycemic control, preferably using CGMs, and mortality among patients with steroid-induced hyperglycemia treated with our protocol versus a control group treated with a standardized protocol for the management of inpatient hyperglycemia.  Patients with COVID-19 and dexamethasone-induced hyperglycemia who were managed using the protocol were more likely to attain glucose levels between 70 and 180 mg/dl during hospitalization and were more likely to have favorable clinical outcomes.

 Patients who were managed according to usual care (i.e. without using the protocol) had a progressive worsening of glycemic control, particularly at the pre-dinner time, throughout their hospitalization.

Clinical Relevance:

The introduction of dexamethasone as a therapeutic option for COVID-19 has raised concerns about its potential negative impact on clinical outcomes of COVID-19. This article presents a protocol to guide the management of dexamethasone-induced hyperglycemia that is associated with a better inpatient glycemic control, improved clinical outcomes, and lower mortality.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

COVID 19 Dashboard: Saudi Arabia

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region

Diabetes is a risk factor for the progression and prognosis of COVID-19

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia inWuhan, China: a single-centered,retrospective, observational study

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

COVID-19 in patients with diabetes: risk factors that increase morbidity

Diabetes and Covid-19 among hospitalized patients in Saudi Arabia: a single-centre retrospective study

Hyperglycemia is Associated With Increased Mortality in Critically Ill Patients With COVID-19

Dexamethasone Reduces Death by up to One Third in Hospitalised Patients With Severe Respiratory Complications of COVID-19

Management of diabetes and hyperglycemia in hospitalized patients

Practical recommendations for the management of diabetes in patients with COVID-19

Diabetic Ketoacidosis in COVID-19: Unique Concerns and Considerations

Newly diagnosed diabetes mellitus, DKA, and COVID-19: Causality or coincidence? A report of three cases

We would like to thank the COVID medical teams at King Saud University Medical City for their efforts in implementing the dexamethasone-induced hyperglycemia protocol in their patient care.

Abbreviations: ICU: intensive care unit. *Analysis was limited to patients who were discharged from the hospital. **Required IV insulin therapy after day 3 of admission. Those who were started on IV insulin within the first 3 days of hospitalization were excluded from the study. † Number of patients with one or more inpatient hypoglycemia event (mild hypoglycemia is defined as a glucose level between 54 and 70 mg/dl and severe hypoglycemia is defined as a glucose level of ≤54 mg/dl) J o u r n a l P r e -p r o o f