key: cord-0858322-gblomokb
authors: Farzadfar, Daniela; Gordon, Caitlyn A.; Falsetta, Keith P.; Calder, Tori; Tsegaye, Adey; Kohn, Nina; Schulman-Rosenbaum, Rifka
title: Assessment of Insulin Infusion Requirements in COVID-19–Infected Patients with Diabetic Ketoacidosis
date: 2022-05-24
journal: Endocr Pract
DOI: 10.1016/j.eprac.2022.05.006
sha: fdc172338ac42d954ca8c99881c70e5d04cc7b72
doc_id: 858322
cord_uid: gblomokb

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is thought to contribute to diabetic ketoacidosis (DKA) and worse outcomes in patients with diabetes. This study compared the cumulative insulin dose required to achieve DKA resolution in the intensive care unit among patients with type 2 diabetes and COVID-19 infection versus without COVID-19 infection. METHODS: This retrospective cohort study evaluated 100 patients—50 patients with COVID-19 in cohort 1 and 50 patients without COVID-19 in cohort 2—treated with insulin infusions for DKA at a tertiary care teaching hospital. The primary outcome was to compare the cumulative insulin dose required to achieve DKA resolution in each cohort. Secondary outcomes included time to DKA resolution, average insulin infusion rate, and average weight-based cumulative insulin infusion dose required to achieve DKA resolution. All endpoints were adjusted for confounders. RESULTS: The mean cumulative insulin dose (units) was 190.3 in cohort 1 versus 116.4 in cohort 2 (P = 0.0038). Patients receiving steroids had a mean time to DKA resolution (hours) of 35.9 in cohort 1 versus 15.6 in cohort 2 (P = 0.0014). In cohort 1 versus cohort 2, the average insulin infusion rate (units/hour) was 7.1 versus 5.3 (P = 0.0025) while the average weight-based cumulative insulin infusion dose (units/kG) was 2.1 versus 1.5 (P = 0.0437), respectively. CONCLUSION: COVID-19–infected patients required a significantly larger cumulative insulin dose, longer time to DKA resolution, higher insulin infusion rate, and higher weight-based insulin infusion dose to achieve DKA resolution versus non-COVID-19–infected patients with type 2 diabetes.

Objective: Coronavirus disease 2019 is thought to contribute to diabetic ketoacidosis (DKA) and worse outcomes in patients with diabetes. This study compared the cumulative insulin dose required to achieve DKA resolution in the intensive care unit among patients with type 2 diabetes and COVID-19 infection versus without COVID-19 infection.

Methods: This retrospective cohort study evaluated 100 patients-50 patients with COVID-19 in cohort 1 and 50 patients without COVID-19 in cohort 2-treated with insulin infusions for DKA at a tertiary care teaching hospital. The primary outcome was to compare the cumulative insulin dose required to achieve DKA resolution in each cohort. Secondary outcomes included time to DKA resolution, average insulin infusion rate, and average weight-based cumulative insulin infusion dose required to achieve DKA resolution. All endpoints were adjusted for confounders. 

In March of 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a global pandemic (1) . Among patients with severe COVID-19 infection, diabetes is one of the most common underlying conditions (2) . Some have suggested that diabetes does not increase the risk of contracting COVID-19, though patients with diabetes have a worse prognosis with the disease, including increased risk of intensive care unit (ICU) admission and mortality (3, 4) .

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) receptors, which are expressed in pancreatic tissue and beta-cells that produce insulin. The impairment in beta-cell function and insulin secretion caused by the virus in addition to the cytokine storm and amplified counter-regulatory hormonal responses by the body may result in the development of diabetic ketoacidosis (DKA) and new-onset diabetes (3) . DKA is a severe metabolic disorder characterized by the build-up of ketones and acidosis. Although DKA is more common in patients with type 1 diabetes, those with type 2 diabetes may also develop ketoacidosis. Precipitating factors include illnesses such as infection or myocardial infarction, omission of or inadequate insulin, or newly diagnosed diabetes (5) .

Pasquel et al. analyzed 5029 patients from 175 U.S. hospitals and examined insulin requirements in patients with and without COVID-19 infection who were also being treated for DKA. COVID-19-infected patients required a significantly higher average insulin infusion rate and longer time to DKA resolution compared with patients without COVID-19 infection (6). Our study attempts to assess whether a difference in insulin requirements between patients with and J o u r n a l P r e -p r o o f without COVID-19 infection being treated for DKA still exists once potential confounders such as steroid use are controlled for. In addition, this study hopes to aid in the growing but currently limited literature relating to diabetes, COVID-19, and DKA.

This was a retrospective, single-center, cohort study that was deemed exempt by the Institutional Review Board and was performed at Long Island Jewish Medical Center (LIJMC), a 583-bed tertiary care teaching hospital that expanded to over 800 beds during the spring 2020 surge of COVID-19. Informed consent was not required as this was a retrospective study. LIJMC was located at the epicenter of the COVID-19 pandemic and, with over 2500 COVID-related hospitalizations from March through mid-June of 2020, it had the second highest number of COVID-19 hospitalizations in New York City (7) . A total of 100 patients with DKA were included in this study with 50 patients in cohort 1 and 50 patients in cohort 2. Cohort 1 included patients with a diagnosis of COVID-19 infection who were admitted from March 1, 2020, to June 30, 2020. Cohort 2 included patients without COVID-19 infection who were admitted from January 1, 2019, to December 31, 2019. Different time periods were selected for cohort 1 and cohort 2, as most patients with DKA who were admitted to LIJMC during 2020 had COVID-19.

In addition, the results of this research would not be influenced by seasonal changes, as the DKA protocol at the institution has remained unchanged during the study period.

J o u r n a l P r e -p r o o f Patients were included if they were 18 years or older with a history of or new diagnosis of type 2 diabetes and were being treated with a continuous insulin infusion for DKA in an ICU setting at LIJMC. Patients were excluded from this study if they had type 1 diabetes, were ruled out for COVID-19 in cohort 1, were pregnant, were not managed with an insulin infusion, were managed for DKA outside of the ICU setting, or were on an insulin infusion for reasons other than DKA.

The primary objective was to compare the cumulative insulin dose (i.e., insulin infusion dose plus initial insulin bolus dose administered prior to insulin infusion plus additional insulin administered during insulin infusion (if applicable)) required to achieve DKA resolution in the ICU among patients with type 2 diabetes and COVID-19 infection versus without COVID-19

infection. The use of an insulin bolus dose prior to insulin infusion was primarily based on provider preference at the institution. In addition, although rare, there were several instances where additional insulin was found to be administered outside of the insulin infusion and was included in the cumulative insulin dose calculations as this insulin may have contributed to DKA resolution. The secondary objectives were to compare the following: time to DKA resolution (hours), average insulin infusion rate (units/hour), average weight-based cumulative insulin infusion dose (units/kG), and average weight-based insulin infusion rate (units/kG/hour) needed to achieve DKA resolution. Safety endpoints included the occurrence of hypoglycemia (blood glucose [BG] < 70 mg/dL) or severe hypoglycemia (BG < 54 mg/dL) during and up to one hour after the insulin infusion ended.

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

Data was collected through a retrospective chart review using electronic medical records. All data was collected and managed using REDCap (Research Electronic Data Capture), a passwordsecure health system database designed to support data collection for research studies and in which all web-based information transmission is encrypted (8, 9) . Data collected included patient demographics; diabetes history; admission diagnoses; baseline DKA labs and labs at resolution; concomitant hyperglycemia-causing medications; medications used for COVID-19 treatment; vasopressor use; cumulative insulin dose (units); insulin infusion data including dose (units and units/kG), rate (units/hour and units/kG/hour), and duration (hours); hypoglycemia episodes during insulin infusion; total length of stay (LOS); and mortality.

DKA was defined as meeting three or more of the following criteria: blood glucose > 250 mg/dL, serum bicarbonate < 15 mmol/L, anion gap (AG) > 15 mmol/L, pH < 7.3, or positive ketonuria or ketonemia (i.e., elevated beta-hydroxybutyrate [BHB]). Patients' blood glucose was highly considered to ensure DKA diagnosis, however, DKA was defined using three or more of the aforementioned criteria to better align with institutional guidelines as well as account for the real-world setting of a pandemic, in which certain lab values may not have been available. DKA resolution was defined as meeting at least two of the following criteria including blood glucose ≤ 250 mg/dL, serum bicarbonate ≥ 15 mmol/L, normal anion gap, pH ≥ 7.3, or negative betahydroxybutyrate (BHB) (10, 11) . To adapt the study to a real-world situation in the setting of a pandemic, the criteria for DKA diagnosis and resolution were adapted accordingly in relation to the cut-off for the anion gap. This was to account for the high patient volumes as well as limited J o u r n a l P r e -p r o o f ICU beds, which in turn led to transitioning patients off the insulin infusion and transferring them from the ICU with higher anion gaps compared to standard practice. If the patient met DKA resolution criteria but the anion gap was not resolved, the cause was assessed. Possible causes for continued anion gap elevation were elevated lactate, uremia or renal failure (i.e., eGFR < 45 mL/min/1.73m 2 ), or starvation ketosis (12) . In terms of the safety endpoints, hypoglycemia was defined as a BG < 70 mg/dL while severe hypoglycemia was defined as a BG < 54 mg/dL (13) .

Concomitant hyperglycemia-causing medications, such as corticosteroids, were assessed; refer to Supplementary Table S1 for the complete list of these medications (14, 15) . For patients receiving steroids, average daily steroid doses were collected and categorized as low dose, medium dose, high dose, very high dose, or pulse therapy; refer to Supplementary Table S2 for the full definitions of each steroid dose category (16) .

For each continuous baseline factor, the Mann-Whitney test was used to examine the association between cohort (COVID-19, non-COVID-19) and that factor. For each categorical baseline factor, the chi-square test (or Fisher's exact test, as appropriate), was used to examine the association between cohort and that factor.

Analysis of Variance (ANOVA) was used to examine the association between COVID-19 infection and each primary and secondary outcome. Possible confounders (including steroid use, norepinephrine use, and the use of other hyperglycemia-causing medications) were identified J o u r n a l P r e -p r o o f prior, and all endpoints were adjusted for these possible confounders. The interaction of each of these factors with cohort was included in each model. If the interaction between the confounder and cohort was significant, pairwise comparisons of the cohorts were carried out within the ANOVA model. For these comparisons, a Bonferroni adjustment was used such that a p-value < 0.0125 was considered statistically significant. Interactions that were not significant were removed from the model. For all outcomes, the log transformation was used to better meet the assumptions of the ANOVA model. Summary statistics are given as adjusted least squares means and their associated 95% confidence intervals calculated from the ANOVA model on the log scale, and they are then transformed back to original scale of measurement. Four subjects died prior to DKA resolution. Therefore, additional analyses using survival methods were carried out for the outcomes: time to resolution of DKA (hours), cumulative insulin dose (units), and average weight-based cumulative insulin infusion dose (units/kG). Specifically, multivariable proportional hazards models were used. Subjects who died prior to resolution of DKA were considered censored in these models. As the results of these analyses did not differ qualitatively from those of the ANOVA models, only the results of the ANOVA models are presented-both for ease of interpretation and for consistency with the analyses of average insulin infusion rate (units/hour) and average weight-based insulin infusion rate (units/kG/hour). The association between hypoglycemia and cohort was examined using the chi-square test. The association between severe hypoglycemia and cohort was examined using the Fisher's exact test. A p-value < 0.05 was considered statistically significant unless otherwise noted.

Hospital length of stay (LOS) was estimated using the Kaplan-Meier product limit method and compared using the log-rank test. Subjects who died in the hospital were considered censored.

Summary statistics are given as median LOS with the associated 95% confidence interval.

A total of 340 patients were identified and screened -94 patients from the cohort 1 time period and 246 patients from the cohort 2 time period. After screening patients, 240 were excluded -44 patients from cohort 1 and 196 patients from cohort 2 with the most common reason for exclusion being the use of an insulin infusion for reasons other than DKA. This left a total of 100 patients who were included in this study with 50 patients in each cohort ( Figure 1 ). There were 21 patients receiving steroids in cohort 1 compared to 5 patients receiving steroids in cohort 2 ( Figure 1 ). The mean (± SD) body mass index (BMI) (kG/m 2 ) in cohort 1 versus cohort 2 was 32.5 (± 8.6) versus 26.6 (± 9.5) (P = 0.0002) ( Table 1 ). In addition, the mean (± SD) hemoglobin A1c (HbA1c) was 10.6% (92 mmol/mol) (± 2.6%) versus 11.8% (105 mmol/mol) (± 2.9%) in cohort 1 versus cohort 2 (P = 0.0394), respectively (Table 1) . Additional baseline characteristics are included in Table 1 . Table S2 ) and illustrates that the majority of patients receiving steroids in cohort 1 (61.9%) were on high-dose steroids.

The adjusted mean cumulative insulin dose in cohort 1 was 190. For time to DKA resolution, the interaction between steroid use and cohort was statistically significant (P = 0.0286), indicating that the association between cohort and time to DKA resolution was affected by steroid use (Table 2) . For this secondary endpoint in particular, a pvalue < 0.0125 was therefore considered statistically significant (Table 3) J o u r n a l P r e -p r o o f Disease severity and progression were assessed using vasopressor data. Vasopressor requirements at baseline (i.e., prior to or at the time that the insulin infusion was started) were used as an indicator of disease severity. Initiation of additional vasopressors during DKA treatment was interpreted as disease progression. In cohort 1, 46% of patients were on a vasopressor at baseline with six of these patients on two or more vasopressors (Table 1 ).

Vasopressors were started or added in 30% of patients in cohort 1 while on the insulin infusion with a total of twelve of thirty-two patients (37.5%) requiring two or more vasopressors during insulin infusion use. In comparison, 8% of patients were on a vasopressor at baseline in cohort 2 with one patient on two or more vasopressors (Table 1 ). Vasopressors were started or added in 10% of patients in cohort 2 while being treated with the insulin infusion with a total of three of seven patients (42.9%) on two or more vasopressors during insulin infusion use.

Disease severity and progression were also measured by assessing dialysis use and intubation at baseline and during insulin infusion. In cohort 1, three patients (6.0%) were on intermittent hemodialysis (IHD) at baseline (i.e., prior to admission) with 14% of patients initiating dialysis during insulin infusion treatment. In comparison, two patients (4.0%) were on IHD at baseline in cohort 2 and dialysis was initiated in 4% of patients during insulin infusion treatment. At baseline (i.e., prior to insulin infusion initiation), thirty patients (60.0%) were intubated in cohort 1 versus seven patients (14.0%) in cohort 2 (P < 0.0001) ( Table 1) . During the insulin infusion, an additional two patients (4.0%) in cohort 1 were intubated versus one patient (2.0%) in cohort 2.

The mortality rate in cohort 1 was 62.0% versus 4.0% in cohort 2 (P < 0.0001). In cohort 1, three of the thirty-one patients that died did so before DKA resolution while 1 of the 2 patients that died in cohort 2 did so before DKA resolution. DKA resolution labs are reported in the Supplementary Material (Supplementary Table S6 ). In cohort 1, twenty-six patients of the fortysix patients with an available anion gap achieved a normal anion gap at the time of resolution.

Among the twenty patients that did not, fourteen patients had an elevated lactate or lactic acidosis, seventeen patients had uremia or renal failure, and one patient had starvation ketosis.

These patients met other criteria for DKA resolution, however. In comparison, three patients among the forty-nine patients for whom an anion gap was available in cohort 2 did not achieve a normal anion gap at DKA resolution. Of these patients, two patients had a mixture of elevated lactate and uremia while one patient experienced only uremia.

COVID-19-infected patients with type 2 diabetes required a significantly larger cumulative insulin dose, longer time to DKA resolution, higher insulin infusion rate, and higher weightbased cumulative insulin infusion dose to achieve DKA resolution when compared with non-COVID-19-infected patients. No significant difference was observed in the weight-based insulin infusion rate (units/kG/h) or incidence of hypoglycemia events between the two cohorts, although a larger number of hypoglycemia and severe hypoglycemia events occurred in cohort 1 compared with cohort 2. Corticosteroid use was associated with a significantly longer time to DKA resolution in the COVID-19 cohort without influencing the results of the other endpoints.

Our study supports the findings of Pasquel et al. and provides additional data on admission diagnoses, race, disease severity markers, and concurrent hyperglycemia-causing medications as J o u r n a l P r e -p r o o f well as COVID-19 therapies, such as corticosteroid use, which was missing in their study (6) .

Baseline characteristics in our study demonstrate that patients in cohort 1 had a significantly higher BMI and lower HbA1c compared with patients in cohort 2. Most patients in cohort 1 and cohort 2 were male with the majority of COVID-19 patients in cohort 1 being African American and having a history of type 2 diabetes mellitus. This aligns with the demographic data portrayed by previous studies such as those cited in the study by Pasquel et al. and in a systematic literature review by Pal et al (6, 17) . As BMI was significantly higher in cohort 1 compared with cohort 2 and a higher BMI may contribute to greater insulin resistance, it would have been preferable to include BMI as a possible confounder in the multivariable models. Ten percent of patients in cohort 1 were missing BMI data, which is likely associated with higher severity of illness; it was not appropriate to include BMI in any of the multivariable analyses considering the missing information was not missing at random and was only missing from one cohort.

An additional difference noted between the two cohorts was the number of endocrine consults completed as cohort 2 had a significantly higher number of endocrine consults compared with cohort 1. Endocrine consults at the institution are usually completed close to the time that patients are transferred out of the ICU, as denoted in Table 1 by the majority of consults being completed after the insulin infusion in cohort 2. Due to high rates of mortality in cohort 1, many patients did not approach being transferred out of the ICU and therefore, did not receive an endocrine consult.

Based on our exploratory findings, clinical outcomes were found to be more adverse in cohort 1 J o u r n a l P r e -p r o o f compared with cohort 2. This was represented by higher rates of mortality and a longer median hospital LOS in the COVID-19 cohort. Previous studies reported DKA mortality in COVID-19 around 45.0% whereas our study reports in-hospital mortality of 62.0% (17) . This could be due to the small sample size and time frame of our study (i.e., prior to the use of dexamethasone 6 mg in COVID-19 patients) (18) . Disease severity and disease progression were also worse in the COVID-19 cohort as represented by vasopressor data, dialysis use, and intubation rates.

Mechanically ventilated patients with COVID-19 and DKA have been shown to have worse outcomes while patients with diabetes have also been shown to have longer lengths of stay compared to patients without diabetes according to previously published case reports (19) .

Limitations of our study include its design as a retrospective chart review completed during a global pandemic where there was deviation from standard documentation, staffing limitations, different staffing ratios, and travel nurses who were not familiar with the electronic medical record or hospital protocols and had to be familiarized with both. Although the DKA protocol had remained unchanged during the study period, real-world implementation may have varied in the setting of a pandemic although the intent of this study was not to assess adherence to the institution's DKA protocol. Furthermore, an additional limitation may be the variability that exists between cohort 1 and cohort 2. Given the limited number of patients with DKA and without COVID-19 during the time period utilized for cohort 1, patients in cohort 1 and cohort 2 were selected from different time periods and therefore, patients in cohort 1 were treated during the initial surge of the pandemic where variability in treatment may have occurred while patients in cohort 2 were not. In addition, patients in cohort 2 were not as severely ill as those in cohort 1.

Finding a comparator group with comparable disease severity, however, was not feasible given J o u r n a l P r e -p r o o f the typical non-COVID-19 patients that present with DKA. The mortality rate in cohort 2, signifying disease severity, is similar to the expected DKA mortality rate in patients without COVID-19 (6) . The small sample size utilized in the study, particularly the small sample of patients on steroids is an additional limitation as the time period utilized in this study was prior to steroids becoming the standard of care for COVID-19 treatment and typically, non-COVID-19 patients with DKA are not on steroids unless required due to underlying disease processes (18) .

Another limitation is that this study was conducted prior to the availability of COVID-19 vaccines and before it was known that there is no evidence to support the use of other tried therapies (e.g., hydroxychloroquine, azithromycin, etc.). Confounders such as the use of concurrent hyperglycemia-causing medications were also present although these were controlled for.

Our findings confirm that patients with COVID-19 and DKA have higher insulin requirements 

Listings of WHO's response to COVID-19. World Health Organization

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention

COVID-19 in people with diabetes: understanding the reasons for worse outcomes

Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome

Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: Clinical and biochemical differences

Characteristics of and mortality associated with diabetic ketoacidosis among US patients hospitalized with or without COVID-19

Hospitals steel for possible virus resurgence, unsure of their financial future

Research electronic data capture (REDCap) -A metadata-driven methodology and workflow process for providing translational research informatics support

The REDCap consortium: Building an international community of software platform partners

Hyperglycemic crises in adult patients with diabetes

Management of adult diabetic ketoacidosis

The serum anion gap is altered in early kidney disease and associates with mortality

Glycemic targets: Standards of medical care in diabetes-2021

Drug-induced glucose alterations part 2: Drug-induced hyperglycemia

Piqray (alpelisib) [prescribing information

NJ: Novartis Pharmaceuticals Corp

Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology

Clinical profile and outcomes in COVID-19 patients with diabetic ketoacidosis: A systematic review of literature

Dexamethasone in hospitalized patients with COVID-19

COVID-19 and diabetic ketoacidosis: Report of eight cases

This work was supported by the Northwell Health COVID-19 Research Consortium in the form of editing support.

The findings of this study confirm that COVID-19-infected patients with DKA have higher insulin requirements versus non-COVID-19-infected patients and suggest that steroid use may result in a longer time to DKA resolution in COVID-19 patients. This suggests that further research is needed to establish the link between COVID-19 and DKA.

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J o u r n a l P r e -p r o o f