Diabetes 1

Managing Hyperglycemia in the COVID-19 Inflammatory Storm

Roma Gianchandani, Nazanene H. Esfandiari, Lynn Ang, Jennifer Iyengar, Sharon Knotts, Palak Choksi, and Rodica Pop-Busui https://doi.org/10.2337/dbi20-0022

A novel coronavirus, severe acute respiratory syndrome In influenza-like illnesses, hyperglycemia has been reported coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 to increase plasma glucose concentration in airway secre- [COVID-19]) is now at global pandemic levels causing tions. Additionally, increased viral replication in vivo and significant morbidity and mortality. Patients with diabetes suppression of the antiviral immune response is also de- are particularly vulnerable and more likely to get severe scribed (9). Increased permeability of the vasculature and complications when infected with this virus. Although the subsequent collapse of alveolar epithelium have direct DIABETES IN PERSPECTIVES information continues to emerge, here we provide our effects on pulmonary function (10) and may explain the perspective on initial outcomes observed in hospitalized higher mortality rates observed in these patients (8). patients with diabetes and the potential role played by the proinflammatory metabolic state in these patients that Hyperglycemia and COVID-19 Infections promotes fertile ground for the virus’ inflammatory The significant hyperglycemia that occurs in the acute surge, resulting in severe insulin resistance and severe fl hyperglycemia. The rapidly evolving renal failure, hypo- in ammatory state of COVID-19 patients has been recog- tension, pressor and steroid use, and variable nutri- nizedandfoundtobepronouncedamongthosewith tional support further complicates their management. diabetes, prediabetes, and/or obesity. A bidirectional link fl Thus, timely implementation of glucose management between chronic in ammation and hyperglycemia had been protocols addressing these complex scenarios while already described for chronic complications of diabetes. For also following COVID-19–related trajectories in inflam- instance, several changes in the immune system including matory biomarkers and being cognizant of the health alterations in specific cytokines and chemokines, shifts in care provider exposure may substantially affect mor- the number and activation state of various leukocyte pop- bidity and mortality. ulations, and increased apoptosis and tissue fibrosis are present in obesity and type 2 diabetes, suggesting that inflammation has an active role in the pathogenesis of A new coronavirus, severe acute respiratory syndrome coro- hyperglycemia, progression to clinically overt type 2 di- navirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID- abetes, and chronic complications (11–14). We believe that 19]) was first reported in late December 2019 in Wuhan, this baseline inflammatory state could set the stage and China (1), and has progressed to become a pandemic with background for further elevations in the levels of inflam- over 3 million cases confirmed (2) and still growing (3). No matory cytokines, particularly as seen in acute infectious specific therapeutic agents have been identified, and its diseases such as COVID-19, further increasing insulin re- infectious nature, hospitalization rates, intensive care sistance, promoting proinflammatory effects of acute admissions, and mortality are very high (2,4–7). Preex- (stress) hyperglycemia, and ultimately leading to a poor isting chronic illnesses such as diabetes, hypertension, and prognosis of such patients with diabetes (15–18). Our obesity result in worst outcomes in the presence of COVID- observations are corroborated by the recent retrospective 19 infection and virus-induced respiratory dysfunction (8). multicentered study of over 7,000 cases of COVID-19 in

Division of Metabolism, Endocrinology and Diabetes, Department of Internal This article is part of a special article collection available at https://diabetes Medicine, University of Michigan, Ann Arbor, MI .diabetesjournals.org/collection/diabetes-and-COVID19-articles. Corresponding author: Roma Gianchandani, [email protected] © 2020 by the American Diabetes Association. Readers may use this article as fi Received 23 April 2020 and accepted 9 July 2020 long as the work is properly cited, the use is educational and not for pro t, and the work is not altered. More information is available at https://www.diabetesjournals This article contains supplementary material online at https://doi.org/10.2337/ .org/content/license. figshare.12631064.

Diabetes Publish Ahead of Print, published online August 11, 2020 2 Hyperglycemia and COVID-19 Inflammatory Storm Diabetes

Figure 1—Examples of randomly selected patients admitted with COVID-19–related pneumonia, acute respiratory distress syndrome, and important surges in inflammatory biomarkers who developed severe hyperglycemia in the presence of cytokine storm. Data are shown for procalcitonin, blood glucose levels, and insulin requirement during the acute inflammatory surge in two randomly selected patients: patient A, well controlled prior to admission on oral antiglycemic agents, and patient B, requiring prior insulin.

Hubei Province, China (17). The authors reported a signif- Although the current information continues to emerge icant correlation between well-controlled blood glucose and and the full impact of severely high peaks in glucose levels lower serum levels of inflammatory markers (interleukin- on disease course and mortality has only recently become 6 [IL-6], high sensitivity C-reactive protein [hsCRP], lactic available, the initial experience we collected since the peak dehyrogenase [LDH]) in patients with COVID-19. A re- of COVID-19 in Michigan suggest that acute and persistent cently reported study in patients with diabetes without surges in blood glucose levels associated with the cytokine advanced chronic complications or comorbidities at base- storm herald poor prognosis. Thus, in conjunction with line supports the marked and rapidly evolving inflamma- management of infection, inflammation, and supportive tory process in the presence of SARS-CoV-2 infection (19). care, a rapidly instituted and tailored glucose management Despite presenting initially with mild symptoms and fever, plan targeting hyperglycemia is critical. This can help pre- the clinical course deteriorated very rapidly with progres- vent and reduce morbidity and complications leading to sive dyspnea and pneumonia with higher computerized prolonged inpatient stay and increased resource utilization tomography imaging severity scores. Compared with patients during these times when most hospitals and health care without diabetes, individuals with diabetes showed higher systems are overwhelmed by the COVID-19 cases (17). elevations in the concentrations of IL-6, ferritin, hsCRP, and Michigan is one of the states with a very high number of D-dimer foreshadowing a raging cytokine storm and a hyper- COVID-19 cases and high rates of complications and mor- coagulable state with rapid deterioration. In addition, the tality. Here we provide a perspective on the Michigan insulin requirements were very high even in those patients Medicine experience and the plans implemented to ef- who were insulin naive prior to admission (19). fectively curb these glucose surges and expedite recovery diabetes.diabetesjournals.org Gianchandani and Associates 3

Table 1—Initial subcutaneous insulin dosing guideline for critically ill COVID-19 patients admitted with high glucose

for patients with diabetes and/or stress hyperglycemia general management plan that also included specified admitted with COVID-19–related illness. laboratory testing to monitor disease activity with a panel of inflammatory and prothrombotic markers was imple- Intervention mented. The overall health care delivery models have A specialized regional isolation containment unit was been transformed significantly, transitioning from the created for the acute care of these patients, and a stepwise classical in-person consult to interprofessional consultations. 4 Hyperglycemia and COVID-19 Inflammatory Storm Diabetes

This model relies on interactive chart reviews and provides prioritized reducing the number of glucose checks as recommendations to the primary teams by diabetes spe- much as safely possible in order to minimize health care cialists with the goal of preserving personal protective providers’ exposures while also conserving PPE. The U.S. equipment (PPE) and reducing exposure for health care Food and Drug Administration recently approved the providers. use of continuous glucose monitors for inpatient glucose Within the very first days of COVID-19 inpatient surge, measurements (22). While this definitely helps in re- a phenotype of severe hyperglycemia was noted in a large ducing exposure and conserving PPE, in our experience, proportion of the critically ill admitted patients carrying their accuracy is not validated in the most critical a prior diagnosis of type 1 diabetes, type 2 diabetes, pre- patients due to superimposed hypotension, use of vaso- diabetes, or severe obesity. Their glucose management was pressors, and possibly high-dose acetaminophen, which further complicated by rapid acute renal failure, tube feed can falsely elevate glucose levels. Additionally, given the initiation, vasopressor support for hypotension, steroids complex care of these patients, the extra burden of for acute respiratory distress syndrome, and chronic renal teaching the use of a new tool on nurses was not replacement therapy. In addition, detailed history of their sustainable. Thus, for convenience, we included arterial diabetes management was limited, as several patients were and venous blood glucose values, which are frequently transferred from other Michigan hospitals not connected drawn in ventilated patients and in patients receiving with our electronic medical records. All these factors high dose of intravenous vitamin C infusion, to replace presented important health care challenges. point-of-care glucose checks, and we reduced the Thus, our major aim was to develop viable algorithms to number of glucose checks to every 6 h in the majority provide a targeted approach to manage hyperglycemia in of cases. To further reduce burden on primary teams, COVID-19–infected patients based on a personalized risk and for timely insulin dose adjustments to parallel stratification that includes different levels of hyperglyce- changes in inflammatory and the rest of disease mia and insulin resistance, prior diabetes control, presence progress markers, our team was performing insulin dose of obesity, needs and type of nutritional support, renal adjustments multiple times a day and was in charge of dysfunction, vasopressor support, and disease activity. writing all insulin orders for inpatient hyperglycemia The University of Michigan Hospital provided care to management. This was a critical component for success, ;500 COVID-19 patients since the COVID-19 crisis hit given the very fluid clinical status of the severely ill southeast Michigan. Approximately 160 out of 500 patients COVID-19 patients, necessitating a very close watch and had known diabetes and were referred to us for management. constant changes in insulin regimens for successful However, some patients who came in critical condition and titrations. had no prior known diabetes also developed hyperglycemia. The tailored protocols developed are described in Tables 1 We also observed that among patients we followed, ;43% and2withoveralltargetedbloodglucosegoalsof150– were African American, which is high but in line with other 180 mg/dL. However, blood glucose levels ,200 mg/dL observations showing a disproportionately high burden of were also targeted in some patients with very labile and severe disease among African Americans (20). The algorithm critical forms of disease, particularly since most were was rapidly developed, and although it continued to be also on continuous tube feeding and thus in a constant refined daily in the first couple of weeks based on the postprandial state. emerging observations by our team, it is fair to state that it For critically ill patients with severe hyperglycemia (blood was used in a more or less refined form in up to 200 patients. glucose .450 or 500 mg/dL), an insulin infusion was In addition, given the very large number of patients we had to initiated with titration often requiring very high rates— follow on a daily basis, we have activated several hyper- up to 12–20 units/h and occasionally up to 40 units/h. Once glycemia management teams to cover all these patients. glucose ranges were within 200–300 mg/dL at lower hourly Preliminary in-house experience has confirmed that the insulin drip rates, we would transition to subcutaneous severity of hyperglycemia and marked insulin resistance insulin as soon as possible given the extenuating health were also associated with a characteristic inflammatory care considerations described above. biomarker signature that includes rapid elevations and Scheduled regular insulin, a sliding scale, and basal changes in the levels of hsCRP, procalcitonin, triglycerides, insulin adequately timed with other nursing interven- IL-6, and D-dimers; thus, these were also included in the tions, especially arterial blood gas checks for ventilator risk stratified approach. Several prior studies have reported settings, helped successfully lower glucose levels into goal that procalcitonin levels may be important predictors for range without increasing nurse contact, thus decreasing a more severe form of disease (17,21). See examples in overall burden and PPE use. Our algorithms to predict two randomly selected patients admitted with COVID-19– labile glucose values with significant hyper- and hypogly- related pneumonia, acute respiratory distress syndrome, and cemia were improved by monitoring the changes in in- important surges in inflammatory biomarkers who developed flammatory biomarkers levels checked by the intensive severe hyperglycemia followed by our team (Fig. 1A and B). care unit (ICU) teams, thus allowing us to prompt up or In the next steps, we created protocols for insulin down titrations of insulin doses more confidently to delivery for nurses entering individual patient rooms. We prevent either further glucose surges or hypoglycemia. diabetes.diabetesjournals.org Gianchandani and Associates 5

Table 2

Given that insulin resistance reduces dramatically as mortality, time to recovery, length of intensive care or apatient’s clinical condition improves, we proactively overall hospital stay, or rate of severe complications as- reduced insulin doses as soon as reductions in inflam- sociated with the algorithm. Lastly, these initial observa- matory biomarkers trends were documented. This flexible tions may only be applicable to patients with phenotypes approach following trends in frequently monitored in- and socioeconomic status similar to those who were ad- flammatory markers to help us guide insulin titrations mitted to the University of Michigan Hospitals. Thus, was a critical part of our evaluation. Our observations and these need to be confirmed in larger and controlled studies developed algorithms were in fact in concordance with that are including the new evidences on disease course, risk the recent publication by HamdyandGabbay(23)out- factors, management, and prognosis of COVID-19 infec- lining a similar experience and administration of regular tion that are emerging globally. insulin every 6 h in the management of diabetes in Strengths of the algorithm are the fact that the con- COVID-19 patients in ICU at the Joslin Diabetes Center. tinuous management of the insulin orders by our diabetes In addition, similar to our Perspective, the recent review team allowed us to proactively and effectively react to by Al-Jaghbeer and Lansang (24) provides broad guidance surges in glucose levels driven by disease activity and in management of hyperglycemia in COVID-19 patients significantly decrease the burden on the primary teams. in ICU. Our Perspective has several limitations. First, the data Conclusion described and the algorithm we have developed are not For the reasons stated above, improving glucose control is a result of a randomized clinical trial or a research study a critical measure to improve outcomes and reduce sec- but instead are based on our direct observations in the ondary infections, renal dysfunction, and therefore ICU patients with severe COVID-19 disease we followed. Thus, stay and ventilator dependence. There is adequate pre- we do not have a control population to compare differ- cedence from prior ICU data about similar associations of ences in outcomes. Second, we acknowledge that given the glycemic control with patient morbidity and survival. We very fluid status associated with this pandemic and the believe that sharing our rapidly accumulated experience rapid rise in the number of severe cases admitted, there are in adjusting insulin regimens to maintain appropriate many confounding factors that we are unable to account glucose levels in conjunction with following trends in for at this time. In addition, we are unable to provide at inflammatory markers could guide glycemic management this time more specific data on the direct effectiveness of for other institutions. In the meanwhile, evaluation of our this algorithm on several important outcomes such as glucose management strategies and their impact on 6 Hyperglycemia and COVID-19 Inflammatory Storm Diabetes outcomes on COVID-19 patients with hyperglycemia is in 11. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat process. Rev Immunol 2011;11:98–107 12. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Acknowledgments. We would like to thank the Endocrinology Consult and Circulation 2002;106:2067–2072 Hospital Intensive Insulin Program faculty, advanced practice providers, faculty, 13. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, and fellows for their contributions, suggestions, and discussions on hyperglycemia interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286: management and care of hyperglycemic COVID-19 patients. This work recognizes 327–334 the efforts of all the health care professionals at Michigan Medicine who are at the 14. Dandona P, Aljada A, Bandyopadhyay A. The potential therapeutic role frontline of this epidemic. of insulin in acute myocardial infarction in patients admitted to intensive Duality of Interest. 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