Approach to Hospital Patient Severe Insulin Resistance JCEM 2011

Approach to the Hospitalized Patient withSevere Insulin Resistance

Jennifer Larsen and Whitney Goldner

University of Nebraska Medical Center, Department of Internal Medicine, Division ofDiabetes, Endocrinology, and Metabolism, Omaha, Nebraska 68198-3020

Glucose control improves outcomes in the hospitalized patient, particularly patientsonprolongedventilator support, after acutemyocardial infarctionor after coronaryartery bypass surgery. An iv insulin algorithm is the standard of care for initial treat-ment of significant hyperglycemia in the hospitalized patient, and it can be transi-tioned to periodic sc insulin once the patient is more stable. However, illness, med-ications, the endocrine and inflammatory response to stress, and pain can allcontribute to insulin resistance and further aggravate preexisting insulin resistancecausedbyobesity.Glucose treatmentgoalshavebeenestablished toguide the1rapy,but achieving those goals can bemore challenging in the presence of severe insulinresistance. When target glucose values are not achieved with established insulinalgorithms, thepractitioner shouldevaluate forpotential causesof insulin resistancefrom technical factors that cause pseudo-insulin resistance as well as other mod-ifiablefactors, suchaselectrolytedisorders,parenteralandenteralnutrition,orothermedications. Publishedglucoseguidelinesprovideglucosegoals toguide changesin the insulin algorithm, but these goalsmay be difficult to achieve in all individuals.Weproposeastepwiseapproachtoevaluateandtreatsevere insulinresistance inthehospitalized patient in order to achieve glucose goals in a timely fashion. (J ClinEndocrinol Metab 96: 26522662, 2011)

A 48-yr-old femalewas admitted for fever and possiblesepsis secondary to a perirectal abscess. She wasunconscious, intubated,andhypotensiveonacatecholamineinfusion in the intensive care unit when consultation for glu-cose management was initiated. She was last seen at the ad-mittinghospital 4yrbeforeadmission, atwhich time shewasreported to have borderline diabetes. Outpatient medica-tions were unknown at the time of admission. Blood sugarwas 692 mg/dl on admission laboratory, temperature was38.5C,bloodpressurewas60/40mmHg,andpulsewas105beats per minute. Body mass index calculated from previ-ously recorded height was 45 kg/cm2. On examination, shewas noted to have acanthosis nigricans around her neck andin both axillae, considerable abdominal obesity, and lowerextremity venous stasis changes with 1 pitting edema. Onthe standard iv insulin algorithm, she was receiving 32 U ofregular insulin per hour, andher bedside capillary bloodglu-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright 2011 by The Endocrine Societydoi: 10.1210/jc.2011-0255 Received January 27, 2011. Accepted May 31, 2011.

Abbreviation: TPN, Total parenteral nutrition.

Accreditation and Credit Designation StatementsThe Endocrine Society is accredited by the AccreditationCouncil for Continuing Medical Education to provide con-tinuingmedical education for physicians. TheEndocrine So-ciety has achieved Accreditation with Commendation.The Endocrine Society designates this Journal-basedCME activity for a maximum of 1 AMA PRA Category 1CreditTM. Physicians should claim only the credit commen-surate with the extent of their participation in the activity.Learning ObjectivesUpon completion of this educational activity, participantsshould be able to: Evaluate potential causes of significant insulin resistance

that can impair the ability to achieve glucose target values Develop potential strategies for addressing insulin resis-

tance in the hospital Convert from intravenous to subcutaneous insulin injec-

tions in the hospitalized patient Apply current guidelines for glucose target values in the

hospitalized patientTarget AudienceThis Journal-based CME activity should be of substantialinterest to endocrinologists and other clinicians caring forhospitalized patients with insulin resistance.Disclosure PolicyAuthors, editors, and Endocrine Society staff involved inplanning this CME activity are required to disclose to learn-ers any relevant financial relationship(s) that have occurredwithin the last 12 months with any commercial interest(s)whose products or services are discussed in the CME con-tent. The Endocrine Society has reviewed all disclosures andresolved or managed all identified conflicts of interest, asapplicable.Disclosures for JCEM Editors are found at http://www.endo-society.org/journals/Other/faculty_jcem.cfm.The following individuals reported NO relevant financialrelationships:Jennifer Larsen, M.D., Whitney Goldner, M.D., and Leon-ard Wartofsky, M.D., reported no relevant financialrelationships.Endocrine Society staff associated with the development ofcontent for this activity reported no relevant financialrelationships.Acknowledgement of Commercial SupportThis activity is not supported by grants, other funds, or in-kind contributions from commercial supporters.Privacy and Confidentiality StatementThe Endocrine Society will record learners personal infor-mation as provided on CME evaluations to allow for issu-ance and tracking of CME certificates. No individual per-formance data or any other personal information collectedfrom evaluations will be shared with third parties.Method of ParticipationThis Journal-based CME activity is available in print andonline as full text HTML and as a PDF that can be viewedand/or printed using Adobe Acrobat Reader. To receiveCME credit, participants should review the learning objec-tives and disclosure information; read the article and reflecton its content; then go to http://jcem.endojournals.org andfind the article, click on CME for Readers, and follow theinstructions to access and complete the post-activity testquestions and evaluation. The estimated time to completethis activity, including review of material, is 1 hour. If youhave questions about this CME activity, please direct themto [email protected] release date: September 2011Activity expiration date: September 2012

S P E C I A L F E A T U R E

A p p r o a c h t o t h e P a t i e n t

2652 jcem.endojournals.org J Clin Endocrinol Metab, September 2011, 96(9):26522662

cose remained over 400mg/dl, despite increasing the insulinper protocol for the previous 4 h.

Background

Importance of glucose control to outcomesGlucose control improves outcomes in the hospital-

ized patient, particularly in the patient with acute myo-cardial infarction, the intensive care unit patient req-uiring prolonged ventilator support, and the patientundergoing coronary artery bypass surgery (15). En-thusiasm for very tight glucose control in the outpatientsetting has been tempered by recent large, multicentertrials. In ACCORD (6), VA-Diabetes Trial (7), andADVANCE (8), intensifying diabetes therapy to achievea lower glucose goal did not reduce cardiovascularevents or overall mortality. In fact, intensification ofdiabetes therapy came with a price, an increased fre-quency of hypoglycemia (911).

The NICE SUGAR Study, the largest inpatient glucosecontrol study to date, was designed to confirm whetherintensive control (glucose, 81108 mg/dl) improves out-comes in the intensive care unit compared with usual care(180 mg/dl). In this study, intensive glucose control in-creased incidence of severe hypoglycemia as well as 90-dmortality (11). This study prompted the modification ofthe current consensus guideline by the American DiabetesAssociation and the American Association of Clinical En-docrinologists,whichnowrecommendsa target glucoseof140180 mg/dl for the majority of critically ill patientsand premeal and randomblood glucose targets below 140and 180 mg/dl, respectively, in all other hospitalized pa-tients (12). What the consensus guideline did not discuss,and has not yet been established, is the optimal strategy bywhich to achieve these guidelines, particularly in thosewith extreme insulin resistance or difficult to control hy-perglycemia. In the end, the risk of hypoglycemia must beweighedagainst thepotential benefits of glucose control in

each individual patient. The glucose goals and treatmentalgorithm should be adjusted based on that assessment.

Causes and mechanisms of severe insulinresistance

Insulin resistance in the hospitalized patient is oftenmultifactorial (Table 1). First, hyperglycemia and insulinresistance can result from the endocrine response tostress. Activation of the sympathetic nervous systemalong with the up-regulation of proinflammatory cyto-kines (13, 14), particularly TNF and nuclear factor-(15), causes a cascade of events, including lipolysis, withincreased free fatty acids (16), activation of the hypotha-lamic-pituitary-adrenal axis and increased cortisol secre-tion, altered insulin signal transduction, and increasedglucose production. The increasing prevalence of obesityin the general population has also increased the frequencyand severity of insulin resistance in and outside the hos-pital, including in the very young (15, 1719). Body massindex also predicts insulin resistance and total insulin re-quirements in the hospitalized patient (20, 21). Many ther-apeutic agents administered to the hospitalized patient, par-ticularly catecholamines, corticosteroids, and enteral andtotal parenteral nutrition (TPN), also contribute to insulinresistance and hyperglycemia. TPN is more likely to causehyperglycemia than enteral nutrition because it bypasses in-cretin-stimulated insulin release (2224). Fat emulsion,whether administered as a source of calories with TPN (e.g.Intralipid) or used as a diluent (e.g. as with propofol, ananesthetic agent used for sedation in the intensive care unit),can also temporarily exacerbate insulin resistance (25). Cor-ticosteroids (26), independentof the routeofadministration,and other immunosuppressant medications, such as tacroli-mus and sirolimus (27, 28), are also well established to con-tribute tohyperglycemia.Otherhormoneproductscancausehyperglycemia by reducing insulin secretion [e.g. octreotide(29)] or inhibiting insulin action [e.g.megestrol acetate (30)usedtostimulateappetite in long-termhospitalizedpatients].

TABLE 1. Causes of insulin resistance in the hospitalized patient

Agent Refs.Stress hormones 13, 14Obesity 1521Electrolyte disorders: hypokalemia, hypocalcemia, hypercalcemia, and hypomagnesemia 4446TPN and enteral nutrition 2224Fatty emulsion (e.g. Intralipid), including medications that are administered in fatty emulsion such as propofol 25Corticosteroids and other immune suppressants (tacrolimus and sirolimus) 2628Anesthetic agents: isoflurane, sevoflurane 4749Hormone products: megestrol acetate (Megace), octreotide, leuprolide (Lupron), bicalutamide 29, 30, 50Hormone disorders: Cushings syndrome, hormone-secreting tumors (e.g. glucagonoma or somatostatinoma),acromegaly, hyperaldosteronism, hyperthyroidism, hypothyroidism, and pheochromocytoma

44, 5154

Other medical illnesses known to contribute to hyperglycemia: pancreatitis, hepatitis C, cystic fibrosis 5558Miscellaneous genetic or other acquired rare causes of insulin resistance: Rabson-Mendenhall syndrome, familialpartial lipodystrophy, congenital generalized lipodystrophy, type A or B insulin resistance syndrome

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Rarely, evaluation of severe insulin resistance can uncoverpreviously unrecognized hormone disorders. In our experi-ence, these factors are additive: obese patients under stresswho require treatment with agents known to exacerbate in-sulin resistance have the most severe insulin resistance andhighest insulin requirements.

Strategies to Identify and Address Causesof Insulin Resistance

If hyperglycemia is severe or persists despite marked in-tensification of the insulin regimen, the clinician shouldinvestigate for potential cause(s) of insulin resistance (Ta-ble 1). A stepwise approach to the severely insulin-resis-tant individual is often required. If a patient is receiving scinsulin and is persistently hyperglycemic despite insulindose escalation and repeated administration of supple-mental insulin, then sc insulin should be discontinued foran iv insulin algorithm. In our experience, sc insulin maybe poorly or variably absorbed in critically ill patients andin those with edema or impaired circulation that results inpoor perfusion of sc tissues. Treatment of all patients withsignificant hyperglycemia should begin with a validated ivinfusion protocol (12). If hyperglycemia persists despite ap-propriate treatment with iv insulin, then an evaluation forcausesofpseudo-insulinresistanceshouldbeinitiated(Ta-ble 2). In some cases, the patient can appear to be resistant toinsulin when the prescribed insulin has not actually reachedthe patient. This can occur when the iv is disconnected,plugged, or intermittently obstructed or the insulin infusionis connected into the maintenance iv far from the patient.Rarely, the insulin resistance occurs suddenly after a new

bag or syringe of insulin is placed, suggesting that the insulinwasnot added.Observed administrationof sc insulin aswellas inspectionof the iv insulin setupcanuncover someof thesetechnical causes of insulin resistance.

Simultaneously, the practitioner should evaluate thepatient for other underlying disorders or medications thatcould contribute to the hyperglycemia and insulin resis-tance (Table 1). In our experience, intermittent hypergly-cemia can occur when a patient is receiving unpredictablenutrition or is intermittently administered a medicationknown to cause or exacerbate hyperglycemia. By evalu-ating the timing of hyperglycemia and comparing it to thetiming of other administeredmedications or solutions, in-cluding those being administered in glucose or fat emul-sion, one can usually uncover the cause. Glucose swingscaused by intermittent medications can be reduced by set-ting specific administration times for these medications,such as corticosteroids, along with prescribed fixed dosesof sc insulin to prevent large glucose swings.

Occasionally, significant hyperglycemia (180 mg/dl)may persist, despite increasing insulin doses, until the se-verity of illness decreases or contributing medications arereduced. In some of these cases, exacerbating factors canbe modified, eliminated, or treated to improve glucoseconcentration or improve insulin resistance (Table 2). Al-though it may not be possible to reduce or withhold allagents known to exacerbate hyperglycemia, understand-ing the potential causes canmake it easier to troubleshootand develop appropriate treatment strategies.

Several strategies can be used to improve glucose controlduring TPN administration. First, adding regular insulin tothe TPN itself can decrease the iv insulin infusion require-

TABLE 2. Approach to the severely insulin-resistant patient

Potential cause Proposed actionExclude causes of pseudo-insulin resistance. Check to see when the hyperglycemia occurred relative to last

initiated bag or syringe of insulin, look at where the insulininfusion is connected to other iv tubing, establish that the iv porthas a good blood return and all connections are tight.

Review current medication list to identify potentialmedications contributing to insulin resistancethat could be modified if appropriate.

For example, if on corticosteroids for presumed adrenal insufficiency,evaluate whether the dose is excessive and could be reduced.

Look for other contributing diseases or electrolytedisorders that should be treated.

Evaluate current electrolytes and review chart for indications of otherdisease (e.g. pancreatitis or other hormone disorders).

Evaluate the number and volume of medicationsbeing given in glucose solution to determinewhether alternative infusions can beconsidered.

Discuss with pharmacy which medications could be administered ina non-glucose solution.

TPN Consider switching to enteral tube feeding if indicated; considerdecreasing glucose concentration or rate of administration;consider adding insulin to TPN solution to reduce amount neededin iv insulin algorithm to reduce risk if TPN suddenly orunexpectedly discontinued.

Intralipid Consider holding for 24 h until severity of illness has improved, otherconditions have been assessed, and treatment initiated.

2654 Larsen and Goldner Severe Insulin Resistance J Clin Endocrinol Metab, September 2011, 96(9):26522662

ments,aswellasdecrease theriskofhypoglycemia if theTPNissuddenlystopped.However,wedonotrecommendaddingmore than half of the total daily insulin requirements to theTPN solution to prevent hypoglycemia if renal function orinsulin requirements rapidly change.Changing fromTPNtoenteral tube feeding as soon as it can be accomplished canreduce insulin requirements (31). Decreasing the iv dextroseconcentration or rate in the TPN or withholding Intralipidcan also improve insulin resistance in the short term.Chang-ingfromafreefattyacidinfusion(e.g. Intralipid) toasoybeanfat supplement has also been described to improve hyper-glycemia, while maintaining desired calories (32). If the pa-tient is already prescribed enteral nutrition, switching to alower carbohydrate or diabetes-specific enteral formula or amonounsaturated fatty acid enteral formula (3335) can re-duce hyperglycemia. However, adding fiber to the enteralformula has not been shown to improve glycemic control (36).

It is just as important to decrease insulin infusion ratesor sc insulin doses as insulin requirements decline. Suddendecreases in insulin requirements can occur with the onsetof acute renal failure, discontinuationofTPN,or changingfrom TPN to enteral tube feeding. In some cases, the al-gorithm should be adjusted down multiple steps ratherthan waiting for multiple episodes of hypoglycemia.

Using the Intravenous Insulin InfusionProtocol

Once the decision has been made to initiate iv insulin, it isimportant to know where iv insulin can be administered ineach hospital. In many hospitals, iv insulin can only be ad-ministeredoncertain floorsor intensive careunits, sopatienttransfer may be required. It is also recommended that a val-idated iv insulin protocol be used (12). The NebraskaMed-ical Center iv insulin algorithm was adapted from and withthe permission ofHirsch and colleagues (37). TheNebraskaMedical Center insulin algorithm and sc insulin order setsshown are in Fig. 1, AC, the latter recently recognized byThe Joint Commission as a best practice model program.

Even with preexisting insulin resistance, we recommendinitiating iv insulin therapy with the lowest algorithm, des-ignated algorithmA in our protocol (Fig. 1). However, withsevere insulin resistance, greater amounts of insulin are re-quired.Theprotocol has been extended to cover theneeds ofthese individuals as shown in Fig. 1B. The nursing staffshould be educated on how to initiate and adjust the insulinalgorithmforglucoseconcentrations thatarehigheror lowerthan the statedglucose target range. It is just as important forthe hospital team to knowhow to run the iv insulin protocoland to discuss in advance and anticipate what to do in situ-ations where insulin requirements might be expected to

change. For example, with interruption of enteral nutritionor new-onset renal failure, the prescribing health care pro-vider should be alerted and a plan initiated to temporarilydecrease or hold the insulin, depending on the specific cir-cumstances and prior glucose concentration.

Titrating the insulin rate more rapidly than recom-mendedby the order set increases the risk of hypoglycemiabyovershooting the glucose target, but itwill not speed thetime to achieve the glucose target. Periodic glucose mon-itoring is essentialwith hourly testing considered opti-mal until a stable insulin infusion rate and glucose con-centration are achieved. Testing should be performed noless frequently than every2h for thedurationof the insulininfusion to minimize wide swings in blood glucose. Theconcept of a glucose target is meant to guide changes ininsulin rates, not that all glucose values have to absolutelyfall in that target range. Progress toward the target glucoseis more important than achieving a glucose target in somepatients, such as those with hyperosmolar coma. Correct-ing the glucose and hyperosmolarity too quickly can in-crease the risk of central pontine myelinolysis (38, 39).

The insulin infusion rate algorithm should be adjusted,not stopped, when glucose values consistently fall belowthe glucose target range but above hypoglycemia (70139mg/dl) to avoid large swings in glucose concentration.

Recognizing and treating hyperglycemia in hospitalizedpatients will occur more quickly with a mandatory glucosesurveillance program.We implemented amandatory nurse-initiated glucose surveillance programonall newly admittedpatients to designated floors. This program identified signif-icant hyperglycemia (180 mg/dl) in 3% of all admittedpatientswithout a history of diabetes and identified the needfor patient education with more rapid initiation of insulintreatment, as recommended by current guidelines.

Transitioning to Subcutaneous Insulin

Once hyperglycemia has improved and stabilized on ivinsulin, transitioning to sc insulin should be the next step.At our institution, we consider transition to sc insulinwhen the majority of the blood sugars are within goal andthe insulin infusion rate or pattern is within one or twosteps using the same iv insulin algorithm for at least thepreceding8h, but preferably24h (Table 3). It is preferableto wait until after any change in medications or plannedintervention that would dramatically change insulin re-quirements, such as discontinuation of TPN. The dailyinsulin requirement canbe calculateddirectly from the last24 h iv insulin infusion.

We have described three scenarios in Table 3: the pa-tientwho is remainingon continuous calories (scenario 1),


the patientwho is being changed from continuous caloriesto an intermittent oral diet (scenario 2), and the patientwho will be changed from continuous to intermittent orovernight enteral tube feeding or TPN (scenario 3). Most

hospitalized patients and all severely insulin-resistant pa-tients will require both a long-acting basal insulin (NPH,detemir, or glargine) and fast-actingbolus insulin (regular,aspart, lispro, or glulisine). Supplemental scale insulin

FIG. 1. Intravenous and sc insulin order forms. The order sets are shown for iv insulin algorithms for initiation (A; levels A to C); for more resistantindividuals (B; levels D to I); and for transition from iv infusion to sc insulin (C).


alone, without a basal insulin, should not be a primarystrategy for glucose control (12). When evaluating whichbasal insulin is preferred,NPHand the long-acting analogglargine were considered equivalent when used in combina-tion with short-acting supplemental insulin for treatment ofpatients on continuous enteral feedings (40). Another con-sideration is that an Intralipid infusionmay require a higherdose of long-acting insulin during the 810 h of its admin-

istration, requiring coordination with the primary or nu-trition support team. Glucose should be monitored us-ing point of care bedside testing at intervals thatcorrespond to the type of nutrition being given, eitherevery 4 h with continuous nutrition or before meals andbedtime for those receiving bolus feeds or meals.

If the patient has been on no nutrition but will be rap-idly transitioning to meals, such as after a recent surgery,

FIG. 1. (Continued).


the calculated requirements while on the insulin infusioncan be used to calculate the basal insulin dose. Bolusinsulin can be added for meals when the patient begins toeat (see scenario 2). In patients eating regular meals, sim-ilar rates of glycemic control andhypoglycemiaoccurwith

daily long-acting (detemir or glargine) plus short-actinginsulin with meals (aspart, lispro, or glulisine) as occurwith split mixed-dose insulin (NPH plus regular) (41).However, we and others prefer short-acting analog in-sulins (aspart, lispro, or glulisine) for meals and sup-

FIG. 1. (Continued).


plemental insulin in the hospital (42) because theirquicker onset and shorter action allow them to be ad-ministered as an insulin:carbohydrate ratio (carb ratio)based on what the patient actually eats to reduce epi-sodes of hypoglycemia in the patient with inconsistentintake or decreased renal function.

In most cases, the insulin dose needed to cover meals isroughly equal to that calculated for the basal insulin re-quirements. There are several ways the meal or bolus in-sulin can be estimated and administered. First, an amountequal to the estimated daily basal rate can be divided intothree equal doses for breakfast, lunch, and supper, assum-ing three equal-sizedmeals.A secondmethod is to estimate

meal requirements from the iv insulin infusion if the pa-tientwas eating during that infusion, as suggested inTable3, scenario 2. In this case, the insulin required over the 34h after a meal, minus the basal insulin rate over the sametime period, is given as a fixed dose or used to calculate acarb ratio. In some cases, the carb ratio used for mealsbefore admission can be applied.A conservativemethod isto assume a carb ratio, where someone assumed to beinsulin sensitive would be given 1 U insulin/15 g carbo-hydrate, whereas an insulin-resistant individual would beassumed to require at least 23 U insulin/15 g carbohy-drate. However, with severe insulin resistance, the ratiocan be much higher, 510 U insulin/15 g carbohydrate.

TABLE 3. Algorithms for transition from iv to sc insulin

Scenario 1 Patient currently on and staying on continuous calories (enteral or parenteral nutrition). Needs basal andsupplemental scale insulin.

Step 1 Estimate 24-h basal insulin requirements from last 24 h of iv insulin or from the number of hoursavailable (e.g. total from last 8 h 3 for estimated 24-h requirement).

Step 2 Choose one of the following options:Option 1 Give one third dose as NPH every 8 h, orOption 2 Give one half dose as glargine or detemir insulin every 12 h, orOption 3 Give full dose as single glargine or determir insulin daily.

Step 3 Continue iv insulin infusion for 3 h after first dose of sc insulin, or less if glucose falls to 100 mg/dl.Step 4 Change from hourly glucose testing to every 4 h glucose testing after iv insulin discontinued to be timed with

the first dose of scheduled long-acting insulin.Step 5 Add a fast-acting analog or regular insulin supplemental scale every 4h (see Fig. 1B order set).Step 6 Adjust scheduled long-acting insulin based on glucose values or consistent need for supplemental insulin as indicated.

Scenario 2 Currently on continuous calories with plans to discontinue and advance to diet as tolerated. Needs basal,bolus (for meals), and supplemental scale insulin.

Step 1 Estimate 24-h basal insulin requirements from new basal requirements after continuous calories have stoppedand before meals have started. A minimum of 45 h may be required (e.g. new insulin rate 3 U/h onaverage for last 3 h to 24 h insulin requirement 3 24 72 U).

Step 2 Choose one of the following options to administer basal insulin:Option 1 Give the entire calculated basal insulin as glargine or detemir as a single daily dose or half in morning and half

at bedtime, orOption 2 Divide calculated basal insulin as NPH twice daily (either two thirds in morning and one third in evening or one

half in morning and one half in evening, depending on pattern suggested during iv insulin).Step 3 Estimate insulin required for meals, orOption 1 Give fast-acting analog or regular insulin at every meal ( snacks) using an insulin:carbohydrate ratio (carb ratio) with

meals. If previous carb ratio is unknown, start with 1 U/15 g, or 23 U/15 g carbohydrate if more insulin resistant, orOption 2 Give fixed dose fast-acting analog or regular insulin with meals. Calculate dose based on insulin required

during meals eaten while on iv insulin, or dose equal to one half calculated morning NPH dose at each meal,assuming a consistent carbohydrate intake at each meal.

Step 4 Continue iv insulin infusion for 3 h after first dose of sc insulin, or less if glucose falls to 100 mg/dl.Step 5 Change from hourly glucose testing to before meal and bedtime glucose testing as soon as iv insulin stopped.Step 6 Add a fast-acting analog or regular insulin supplemental scale at meals (see Fig. 1B order set). Glucose is often checked at

0200 to 0300 h, the first one or two nights after transition to moni to r for nocturnal hypoglycemia, as well.Step 7 Adjust scheduled long- and short-acting insulins based on glucose values or consistent need for supplemental

insulin as indicated.Scenario 3 Currently on continuous calories and plans to change to intermittent or overnight enteral tube feeding or TPN.Step 1 Estimate 24-h basal insulin requirements as with scenario 1 or 2 above.Step 2 Choose one of the following options:Option 1 Bolus tube feedings. Add bolus fast-acting insulin at the time of planned tube feeding based on the

carbohydrate content and volume of formula, and a calculated carb ratio to be determined as describedunder scenario 2, option 1; or

Option 2 Scheduled overnight tube feeding. Administer an additional dose of NPH, which can be incorporated into thescheduled evening dose if appropriate, with an additional 510 U of fast-acting analog or regular insulin atthe start of the scheduled tube feed. Measure glucose at the start, at 0300 h, and at the conclusion of thetube feed and adjust insulin accordingly. If the patient is eating during the day, as well, cover that food withadditional fast-acting regular or analog insulin based on the carb ratio.

A stepwise approach is provided for the most common clinical scenarios.


Some hospitals provide the carbohydrate content of foodson the meal ticket, allowing the patient or the nurse toassess carbohydrate intake of the meal and dose insulinaccording to a prescribed carb ratio. This is particularlyuseful for patients who are eating inconsistently.

Insulin requirements can change rapidly with changingrenal function, stress, activity, food consumption, ormed-ications, particularly in the severely insulin-resistant pa-tient. New-onset hypoglycemia should prompt an assess-ment of renal function or change in iv or enteral nutritionrate or carbohydrate content. Likewise, intermittent epi-sodes of hyperglycemia should prompt questions aboutmedications being infused, inconsistent eating, or addi-tional uncovered food or snacks being purchased orbrought in by family or friends. On demand meal or-dering, available in many hospitals, also allows continu-ous eating behavior that may be more difficult to assessand cover with bolus insulin, increasing the risk forstacking insulin doses, and later hypoglycemia.

Intermittent corticosteroid doses can be covered withadditional timed sc insulin.We often use sc NPH timed toa daily or every other day iv or oral dose of corticosteroids.In this way, the NPH dose can be tapered with the corti-costeroid dose, independent of other scheduled insulindoses. However, meal-time insulin doses may also need tobe increased for the 48 h after a very high dose of cor-ticosteroid, then tapered as the steroids taper.

Controversies and Areas of Uncertainty

In general, oral hypoglycemic agents are discontinued ifpreviously prescribed and are not recommended for treat-ment of new hyperglycemia in the hospitalized patient be-cause of the many contraindications encountered in thissetting. However, once the patient is stable and particu-larly in preparation for discharge, oral insulin-sensitizingagents (i.e. thiazolidinedione or metformin) in particularcan have a significant impact on total insulin requirementsin the severely insulin-resistant patient. However, a thor-ough evaluation for potential contraindications (e.g. planfor iv contrast, fluctuating renal or cardiac status) shouldbe completed before initiation of therapy.

U500 regular insulin has been used in patients withsevere insulin resistance and daily insulin requirements ofat least 200 U of U100 insulin per day (43). However,becauseU500 insulin is dosed differently thanU100, thereis considerable concern about greater risk of serious in-sulin errors without proper nursing, patient, and physi-cian education if used in the hospital. For this reason, wedont recommend routine use of U500 insulin in the hos-pitalized patient at this time, even if it is being prescribed

before admission, at least until the daily requirements canbe confirmed using U100 insulin.

Use of sc insulin pumps in the hospital is another areaof uncertainty. When the patient is unable to make deci-sions about their pump themselves, we discontinue sc in-sulinpump therapyand initiate either iv insulin infusionorsc long-acting basal insulinwith short-acting bolus insulinat meals until the patient is deemed capable of managingtheir pump again without aid. Settings where this shouldbe considered includeanyonewith severe illness (e.g. in theintensive care unit), undergoing or immediately after an-esthesia, with evidence of confusion or disorientation, orreceiving treatment with a medication known to impairjudgment such as narcotics.

Returning to the Patient

Blood cultures grew out gram-negative organisms. The pa-tient was given iv antibiotics, was taken to surgery for inci-sion and drainage of the abscess, and received fluid resusci-tation. Within 24 h, she was weaned off iv catecholamines.Despite clinical improvement, her insulin requirements re-mainedgreater than20U/h,andglucoseremainedabove200mg/dl.The iv infusionwasbeingadministeredappropriately,and no additional electrolyte or contributing medical ill-nesseswere identified. The only other prescribedmedicationwas continuous TPN.We added 50U to the next 24-h TPNinfusion bag and continued her iv insulin infusion.With thisadditional insulin and improved infection, her iv insulin re-quirements and blood glucose improved dramatically. Be-fore extubation, she required 10 U regular insulin/h iv, witha glucose range of 130170 mg /dl. Once extubated, sheinformedus that shehadpreviously been takingdetemir 120Utwicedailyandaspart25U/15gcarbohydrate serving.Herhigh insulin requirements before admission are consistentwith and would predict that she may require even higherdoses of insulin during her hospital course, even with tran-sition back to sc insulin.When a diet was ordered,we addedaspart insulinat25U/15gcarbohydrateservingandchangedher long-acting sc insulin to detemir 120 U twice daily, cal-culated from her iv insulin requirements. Three hours afterthe first dose of detemir, the iv infusion was discontinued,andwe added a supplemental scale of aspart insulin atmealsinaddition toher carb ratio.Bloodglucosevalueswere120130 mg/dl in the morning and 150200 mg/dl at bedtime.Insulin was adjusted based on glucose values through theremainder of the hospitalization. Because edema had in-creased during the hospitalization, thiazolidinediones werenot added, and metformin was not restarted until she wasstable after hospital discharge.


Conclusions

Achieving glucose control in the patient with severe insulinresistance requires a strategic approach. The optimal dosingstrategy and insulin requirements will vary with changingacuity, nutrition, activity, and medications (type, dose, andtiming). Education of all health care staff is needed to safelyuse an iv insulin algorithm to achieve glucose targets in thehospital setting. Just as important, all providers and consul-tantsneed tocommunicatewitheachotherandactasa team,alerting other team members when changes are anticipated(e.g. going to the operating room, discontinuing TPN orother nutrition). There are significant risks of both hyper-glycemia and hypoglycemia in the hospitalized patient, par-ticularly in the severely insulin-resistant patient who is morelikely to experience sudden changes in insulin requirements.Patient safety must be considered before any other stated orpublished consensus statement or goal. If the health careteam feels a lower glucose goal can be achieved safely andwould be beneficial to that patients outcome or if frequenthypoglycemia results from the current algorithm and goals,the algorithm and goals should be adjusted accordingly.

Acknowledgments

Address all correspondence and requests for reprints to: JenniferLarsen, M.D., Department of Internal Medicine, 983020 Ne-braskaMedical Center, Omaha,Nebraska 68198-3020. E-mail:[email protected].

Disclosure Summary: The authors have nothing to declare.

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