Managing Hyperglycemia in the COVID-19 InflammatoryStormRoma Gianchandani, Nazanene H. Esfandiari, Lynn Ang, Jennifer Iyengar, Sharon Knotts, Palak Choksi, andRodica Pop-Busui

https://doi.org/10.2337/dbi20-0022

A novel coronavirus, severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) (coronavirus disease 2019[COVID-19]) is now at global pandemic levels causingsignificant morbidity and mortality. Patients with diabetesare particularly vulnerable and more likely to get severecomplications when infected with this virus. Although theinformation continues to emerge, here we provide ourperspective on initial outcomes observed in hospitalizedpatients with diabetes and the potential role played by theproinflammatory metabolic state in these patients thatpromotes fertile ground for the virus’ inflammatorysurge, resulting in severe insulin resistance and severehyperglycemia. The rapidly evolving renal failure, hypo-tension, pressor and steroid use, and variable nutri-tional support further complicates their management.Thus, timely implementation of glucose managementprotocols addressing these complex scenarios whilealso following COVID-19–related trajectories in inflam-matory biomarkers and being cognizant of the healthcare provider exposure may substantially affect mor-bidity and mortality.

A new coronavirus, severe acute respiratory syndrome coro-navirus 2 (SARS-CoV-2) (coronavirus disease 2019 [COVID-19]) was first reported in late December 2019 in Wuhan,China (1), and has progressed to become a pandemic withover 3 million cases confirmed (2) and still growing (3). Nospecific therapeutic agents have been identified, and itsinfectious nature, hospitalization rates, intensive careadmissions, and mortality are very high (2,4–7). Preex-isting chronic illnesses such as diabetes, hypertension, andobesity result in worst outcomes in the presence of COVID-19 infection and virus-induced respiratory dysfunction (8).

In influenza-like illnesses, hyperglycemia has been reportedto increase plasma glucose concentration in airway secre-tions. Additionally, increased viral replication in vivo andsuppression of the antiviral immune response is also de-scribed (9). Increased permeability of the vasculature andsubsequent collapse of alveolar epithelium have directeffects on pulmonary function (10) and may explain thehigher mortality rates observed in these patients (8).

Hyperglycemia and COVID-19 InfectionsThe significant hyperglycemia that occurs in the acuteinflammatory state of COVID-19 patients has been recog-nized and found to be pronounced among those withdiabetes, prediabetes, and/or obesity. A bidirectional linkbetween chronic inflammation and hyperglycemia had beenalready described for chronic complications of diabetes. Forinstance, several changes in the immune system includingalterations in specific cytokines and chemokines, shifts inthe number and activation state of various leukocyte pop-ulations, and increased apoptosis and tissue fibrosis arepresent in obesity and type 2 diabetes, suggesting thatinflammation has an active role in the pathogenesis ofhyperglycemia, progression to clinically overt type 2 di-abetes, and chronic complications (11–14). We believe thatthis baseline inflammatory state could set the stage andbackground for further elevations in the levels of inflam-matory cytokines, particularly as seen in acute infectiousdiseases such as COVID-19, further increasing insulin re-sistance, promoting proinflammatory effects of acute(stress) hyperglycemia, and ultimately leading to a poorprognosis of such patients with diabetes (15–18). Ourobservations are corroborated by the recent retrospectivemulticentered study of over 7,000 cases of COVID-19 in

Division of Metabolism, Endocrinology and Diabetes, Department of InternalMedicine, University of Michigan, Ann Arbor, MI

Corresponding author: Roma Gianchandani, romag@umich.edu

Received 23 April 2020 and accepted 9 July 2020

This article contains supplementary material online at https://doi.org/10.2337/figshare.12631064.

This article is part of a special article collection available at https://diabetes.diabetesjournals.org/collection/diabetes-and-COVID19-articles.

© 2020 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit, and thework is not altered. More information is available at https://www.diabetesjournals.org/content/license.

Diabetes 1

PERSPECTIVES

INDIA

BETES

Diabetes Publish Ahead of Print, published online August 11, 2020

Hubei Province, China (17). The authors reported a signif-icant correlation between well-controlled blood glucose andlower serum levels of inflammatory markers (interleukin-6 [IL-6], high sensitivity C-reactive protein [hsCRP], lacticdehyrogenase [LDH]) in patients with COVID-19. A re-cently reported study in patients with diabetes withoutadvanced chronic complications or comorbidities at base-line supports the marked and rapidly evolving inflamma-tory process in the presence of SARS-CoV-2 infection (19).Despite presenting initially with mild symptoms and fever,the clinical course deteriorated very rapidly with progres-sive dyspnea and pneumonia with higher computerizedtomography imaging severity scores. Compared with patientswithout diabetes, individuals with diabetes showed higherelevations in the concentrations of IL-6, ferritin, hsCRP, andD-dimer foreshadowing a raging cytokine storm and a hyper-coagulable state with rapid deterioration. In addition, theinsulin requirements were very high even in those patientswho were insulin naive prior to admission (19).

Although the current information continues to emergeand the full impact of severely high peaks in glucose levelson disease course and mortality has only recently becomeavailable, the initial experience we collected since the peakof COVID-19 in Michigan suggest that acute and persistentsurges in blood glucose levels associated with the cytokinestorm herald poor prognosis. Thus, in conjunction withmanagement of infection, inflammation, and supportivecare, a rapidly instituted and tailored glucose managementplan targeting hyperglycemia is critical. This can help pre-vent and reduce morbidity and complications leading toprolonged inpatient stay and increased resource utilizationduring these times when most hospitals and health caresystems are overwhelmed by the COVID-19 cases (17).

Michigan is one of the states with a very high number ofCOVID-19 cases and high rates of complications and mor-tality. Here we provide a perspective on the MichiganMedicine experience and the plans implemented to ef-fectively curb these glucose surges and expedite recovery

Figure 1—Examples of randomly selected patients admitted with COVID-19–related pneumonia, acute respiratory distress syndrome, andimportant surges in inflammatory biomarkers who developed severe hyperglycemia in the presence of cytokine storm. Data are shownfor 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.

2 Hyperglycemia and COVID-19 Inflammatory Storm Diabetes

for patients with diabetes and/or stress hyperglycemiaadmitted with COVID-19–related illness.

InterventionA specialized regional isolation containment unit wascreated for the acute care of these patients, and a stepwise

general management plan that also included specifiedlaboratory testing to monitor disease activity with a panelof inflammatory and prothrombotic markers was imple-mented. The overall health care delivery models havebeen transformed significantly, transitioning from theclassical in-person consult to interprofessional consultations.

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

diabetes.diabetesjournals.org Gianchandani and Associates 3

This model relies on interactive chart reviews and providesrecommendations to the primary teams by diabetes spe-cialists with the goal of preserving personal protectiveequipment (PPE) and reducing exposure for health careproviders.

Within the very first days of COVID-19 inpatient surge,a phenotype of severe hyperglycemia was noted in a largeproportion of the critically ill admitted patients carryinga prior diagnosis of type 1 diabetes, type 2 diabetes, pre-diabetes, or severe obesity. Their glucose management wasfurther complicated by rapid acute renal failure, tube feedinitiation, vasopressor support for hypotension, steroidsfor acute respiratory distress syndrome, and chronic renalreplacement therapy. In addition, detailed history of theirdiabetes management was limited, as several patients weretransferred from other Michigan hospitals not connectedwith our electronic medical records. All these factorspresented important health care challenges.

Thus, our major aim was to develop viable algorithms toprovide a targeted approach to manage hyperglycemia inCOVID-19–infected patients based on a personalized riskstratification that includes different levels of hyperglyce-mia and insulin resistance, prior diabetes control, presenceof obesity, needs and type of nutritional support, renaldysfunction, vasopressor support, and disease activity.

The University of Michigan Hospital provided care to;500 COVID-19 patients since the COVID-19 crisis hitsoutheast Michigan. Approximately 160 out of 500 patientshad known diabetes andwere referred to us formanagement.However, some patients who came in critical condition andhad no prior known diabetes also developed hyperglycemia.We also observed that among patients we followed, ;43%were African American, which is high but in line with otherobservations showing a disproportionately high burden ofsevere disease among African Americans (20). The algorithmwas rapidly developed, and although it continued to berefined daily in the first couple of weeks based on theemerging observations by our team, it is fair to state that itwas used in amore or less refined form in up to 200 patients.In addition, given the very large number of patients we had tofollow on a daily basis, we have activated several hyper-glycemia management teams to cover all these patients.

Preliminary in-house experience has confirmed that theseverity of hyperglycemia and marked insulin resistancewere also associated with a characteristic inflammatorybiomarker signature that includes rapid elevations andchanges in the levels of hsCRP, procalcitonin, triglycerides,IL-6, and D-dimers; thus, these were also included in therisk stratified approach. Several prior studies have reportedthat procalcitonin levels may be important predictors fora more severe form of disease (17,21). See examples intwo randomly selected patients admitted with COVID-19–related pneumonia, acute respiratory distress syndrome, andimportant surges in inflammatory biomarkers who developedsevere hyperglycemia followed by our team (Fig. 1A and B).

In the next steps, we created protocols for insulindelivery for nurses entering individual patient rooms. We

prioritized reducing the number of glucose checks asmuch as safely possible in order to minimize health careproviders’ exposures while also conserving PPE. The U.S.Food and Drug Administration recently approved theuse of continuous glucose monitors for inpatient glucosemeasurements (22). While this definitely helps in re-ducing exposure and conserving PPE, in our experience,their accuracy is not validated in the most criticalpatients due to superimposed hypotension, use of vaso-pressors, and possibly high-dose acetaminophen, whichcan falsely elevate glucose levels. Additionally, given thecomplex care of these patients, the extra burden ofteaching the use of a new tool on nurses was notsustainable. Thus, for convenience, we included arterialand venous blood glucose values, which are frequentlydrawn in ventilated patients and in patients receivinghigh dose of intravenous vitamin C infusion, to replacepoint-of-care glucose checks, and we reduced thenumber of glucose checks to every 6 h in the majorityof cases. To further reduce burden on primary teams,and for timely insulin dose adjustments to parallelchanges in inflammatory and the rest of diseaseprogress markers, our team was performing insulin doseadjustments multiple times a day and was in charge ofwriting all insulin orders for inpatient hyperglycemiamanagement. This was a critical component for success,given the very fluid clinical status of the severely illCOVID-19 patients, necessitating a very close watch andconstant changes in insulin regimens for successfultitrations.

The tailored protocols developed are described in Tables 1and 2 with overall targeted blood glucose goals of 150–180 mg/dL. However, blood glucose levels ,200 mg/dLwere also targeted in some patients with very labile andcritical forms of disease, particularly since most werealso on continuous tube feeding and thus in a constantpostprandial state.

For critically ill patients with severe hyperglycemia (bloodglucose .450 or 500 mg/dL), an insulin infusion wasinitiated with titration often requiring very high rates—up to 12–20 units/h and occasionally up to 40 units/h. Onceglucose ranges were within 200–300 mg/dL at lower hourlyinsulin drip rates, we would transition to subcutaneousinsulin as soon as possible given the extenuating healthcare considerations described above.

Scheduled regular insulin, a sliding scale, and basalinsulin adequately timed with other nursing interven-tions, especially arterial blood gas checks for ventilatorsettings, helped successfully lower glucose levels into goalrange without increasing nurse contact, thus decreasingoverall burden and PPE use. Our algorithms to predictlabile glucose values with significant hyper- and hypogly-cemia were improved by monitoring the changes in in-flammatory biomarkers levels checked by the intensivecare unit (ICU) teams, thus allowing us to prompt up ordown titrations of insulin doses more confidently toprevent either further glucose surges or hypoglycemia.

4 Hyperglycemia and COVID-19 Inflammatory Storm Diabetes

Given that insulin resistance reduces dramatically asa patient’s clinical condition improves, we proactivelyreduced insulin doses as soon as reductions in inflam-matory biomarkers trends were documented. This flexibleapproach following trends in frequently monitored in-flammatory markers to help us guide insulin titrationswas a critical part of our evaluation. Our observations anddeveloped algorithms were in fact in concordance withthe recent publication by Hamdy and Gabbay (23) out-lining a similar experience and administration of regularinsulin every 6 h in the management of diabetes inCOVID-19 patients in ICU at the Joslin Diabetes Center.In addition, similar to our Perspective, the recent reviewby Al-Jaghbeer and Lansang (24) provides broad guidancein management of hyperglycemia in COVID-19 patientsin ICU.

Our Perspective has several limitations. First, the datadescribed and the algorithm we have developed are nota result of a randomized clinical trial or a research studybut instead are based on our direct observations in thepatients with severe COVID-19 disease we followed. Thus,we do not have a control population to compare differ-ences in outcomes. Second, we acknowledge that given thevery fluid status associated with this pandemic and therapid rise in the number of severe cases admitted, there aremany confounding factors that we are unable to accountfor at this time. In addition, we are unable to provide atthis time more specific data on the direct effectiveness ofthis algorithm on several important outcomes such as

mortality, time to recovery, length of intensive care oroverall hospital stay, or rate of severe complications as-sociated with the algorithm. Lastly, these initial observa-tions may only be applicable to patients with phenotypesand socioeconomic status similar to those who were ad-mitted to the University of Michigan Hospitals. Thus,these need to be confirmed in larger and controlled studiesthat are including the new evidences on disease course, riskfactors, management, and prognosis of COVID-19 infec-tion that are emerging globally.

Strengths of the algorithm are the fact that the con-tinuous management of the insulin orders by our diabetesteam allowed us to proactively and effectively react tosurges in glucose levels driven by disease activity andsignificantly decrease the burden on the primary teams.

ConclusionFor the reasons stated above, improving glucose control isa critical measure to improve outcomes and reduce sec-ondary infections, renal dysfunction, and therefore ICUstay and ventilator dependence. There is adequate pre-cedence from prior ICU data about similar associations ofglycemic control with patient morbidity and survival. Webelieve that sharing our rapidly accumulated experiencein adjusting insulin regimens to maintain appropriateglucose levels in conjunction with following trends ininflammatory markers could guide glycemic managementfor other institutions. In the meanwhile, evaluation of ourglucose management strategies and their impact on

Table 2

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outcomes on COVID-19 patients with hyperglycemia is inprocess.

Acknowledgments.We would like to thank the Endocrinology Consult andHospital Intensive Insulin Program faculty, advanced practice providers, faculty,and fellows for their contributions, suggestions, and discussions on hyperglycemiamanagement and care of hyperglycemic COVID-19 patients. This work recognizesthe efforts of all the health care professionals at Michigan Medicine who are at thefrontline of this epidemic.Duality of Interest. No potential conflicts of interest relevant to this articlewere reported.

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