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A rare case of diabetic ketoacidosis presenting with severe hypertriglyceridemia requiring plasmapheresis in an adult with type-2 diabetes mellitus

Case report.

Editor(s): Saranathan., Maya

a Internal Medicine Residency Program, UPMC Pinnacle Harrisburg Hospital

b Penn State College of Medicine, Hershey, PA.

∗Correspondence: Pooja Roy, Internal Medicine Residency Program, UPMC Pinnacle Harrisburg Hospital, 301 Chestnut St, #806, Harrisburg, PA 17101 (e-mail: [email protected] ).

Abbreviations: CT = computerized tomography, DKA = diabetic ketoacidosis, DM = diabetes mellitus, HTG = hypertriglyceridemia, VLDL = very low-density lipoprotein.

How to cite this article: Roy P, Koetter P, Cunningham J, Komanduri S, Cinicola J. A rare case of diabetic ketoacidosis presenting with severe hypertriglyceridemia requiring plasmapheresis in an adult with type-2 diabetes mellitus: case report. Medicine . 2021;100:23(e26237).

The patient was provided and granted informed consent for publication of the case.

The authors have no funding and conflicts of interest to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

Introduction: 

Severe hypertriglyceridemia (HTG) is a rare complication of insulin resistance. Its presentation with diabetic ketoacidosis (DKA) has been reported in a few cases, where most patients have type-1 diabetes mellitus (DM). Our case represents a unique presentation of DKA associated with severe HTG above 10,000 mg/dL in an adult with type-2 DM.

Patient concerns and diagnosis: 

Case Report: A 51-year-old man with no prior illnesses presented to the emergency department with abdominal pain and nausea. He was found to have DKA with a blood glucose level of 337 mg/dL, pH of 7.17, beta-hydroxybutyrate of 7.93 mmol/L, and anion gap of 20 mmol/L. His triglyceride levels were >10,000 mg/dL. His serum was found to be lipemic. Computerized tomography scan of the abdomen demonstrated mild acute pancreatitis. Negative GAD65 antibodies supported the diagnosis of type-2 DM.

Interventions and outcomes: 

Endocrinology was consulted and one cycle of albumin-bound plasmapheresis was administered. This therapy significantly improved his HTG. DKA gradually resolved with insulin therapy as well. He was discharged home with endocrinology follow-up.

Conclusion: 

This unique case highlights an uncommon but critical consequence of uncontrolled DM. It brings forth the possibility of severe HTG presenting as a complication of uncontrolled type-2 DM. Severe HTG commonly presents with acute pancreatitis, which can be debilitating if not managed promptly. Most patients with this presentation are managed with insulin infusion. The use of plasmapheresis for management of severe HTG has not been well studied. Our case supports the use of plasmapheresis as an effective and rapid treatment for severe HTG.

1 Introduction

Hypertriglyceridemia (HTG) is defined as triglyceride levels of >150 mg/dL (>1.7 mmol/L) and further classified into moderate and severe HTG with defining levels of 150 to 885 mg/dL and above 885 mg/dL, respectively. [1] The etiology of HTG is multifactorial, and includes insulin resistance disorders, certain medications, that is, estrogens and bile sequestrants, and renal disease. However, severe HTG is mostly attributed to genetic causes such as familial chylomicronemia or type V hyperlipoproteinemia. [1] Clinical manifestations of HTG vary based on its severity and etiology. Xanthomas and xanthelasmas are commonly seen in patients with hereditary disorders. Pancreatitis is another common presentation, with the risk of development between 10% and 20% in those with triglyceride levels of >2000 mg/dL. [1] In rare cases, patients with HTG-induced pancreatitis present with diabetic ketoacidosis (DKA). In these cases, in which DKA induced HTG, triglyceride levels usually do not exceed 1500 mg/dL. [2,3] There are 2 reported cases where triglyceride levels exceed 10,000 mg/dL. [4,5] In both of these known cases, the patients were young and had a history of type-1 diabetes mellitus (DM). [4,5] We present a unique case of DKA-induced severe HTG in a middle-aged adult without type-1 DM.

The patient is a 51-year-old Hispanic man with no past medical history who presented to the emergency department with abdominal pain and nausea. His symptoms started 2 weeks prior with a burning sensation during urination, associated with polydipsia and polyuria. Three days later, he developed abdominal pain in the periumbilical region. The pain was nonradiating and continued to worsen until he was unable to eat. This was associated with nausea and constipation. He denied fevers or chills. He had no history of abdominal surgery or family history of diabetes or lipid disorders. His body mass index was 26.34 kg/m 2 and he consumed 6 to 12 beers on the weekend. His examination findings were only significant for left upper quadrant abdominal tenderness. The patient was found to have severe HTG, with levels reported in Table 1 . Low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels could not be calculated due to elevated triglycerides. In addition, the patient was hyperglycemic, with a blood glucose of 337 mg/dL and a glycated hemoglobin of 14.9%. An elevated anion gap metabolic acidosis was present with increased serum ketones, suggestive of DKA ( Table 1 ). GAD-65 antibody was negative (<5 IU/mL), making type-1 diabetes less likely. Patient's islet cell antibody screen was not performed as the specimen was hyperlipemic. Urinalysis revealed a urine glucose of >1000 mg/dL and mild ketonuria (40 mg/dL). Lactic acid was mildly elevated at 2.6 U/L. Though lipase level was normal (43 U/L), computerized tomography scan of the abdomen demonstrated findings suggestive of mild acute pancreatitis. To note, the patient's serum was found to be milky in appearance. The patient was started on insulin and potassium chloride infusions and was transferred to the intensive care unit. After consulting endocrinology, one session of plasmapheresis was performed, which improved the patient's triglycerides gradually to 323 mg/dL. Fenofibrate was administered. The patient's blood glucose improved and subsequently he was transitioned to subcutaneous insulin. Triglyceride and cholesterol levels improved, as reported in Table 1 . In addition, the apolipoprotein profile suggested an increased risk of atherosclerosis ( Table 1 ). The patient was stable to be discharged with follow up with his primary care physician and endocrinologist.

3 Discussion

According to the National Health and Nutrition Examination Survey, only <1% of American adults not treated with statins had triglyceride levels >1000 mg/dL. [6] There are also ethnic differences in triglyceride levels, with non-Hispanic blacks having lower triglyceride levels than non-Hispanic whites and Mexican Americans. [7] Diabetic ketoacidosis, however, is a common complication amongst type-1 diabetics, with cases amongst type-2 diabetics rising. [8] DKA is associated with an increase in triglyceride levels, observed in approximately 30% to 50% of cases. [9] Most cases have triglyceride levels of <1000 mg/dL. [2,3] In reported cases, patients with triglyceride levels higher than 10,000 mg/dL were younger than 21-years-old and had a history of type-1 DM ( Table 2 ). [4,5]

The pathophysiology behind DKA-induced HTG is based on insulin resistance or deficiency. When the body lacks insulin or is resistant to insulin, lipolysis occurs, leading to the release of free fatty acids. [4] The increased uptake of free fatty acids into the liver results in a greater production of VLDL, which is eventually converted to triglycerides. Insulin deficiency impedes the activity of lipoprotein lipase, thus interfering with triglyceride metabolism and VLDL catabolism. [10]

Severe HTG increases a patient's risk of acute pancreatitis. This disease can be devastating, with complications such as septic shock and multiorgan failure. Chronically elevated levels of triglyceride are also associated with a higher risk of atherosclerotic cardiovascular disease. [1] Hence it is vital that severe HTG is promptly managed.

The management of HTG begins with lifestyle modifications. Recommendations include weight loss, dietary changes and avoidance of alcohol. Those with moderate triglyceride levels, between 150 and 885 mg/dL, do not have a significant risk of pancreatitis. Thus, these patients can be started on statins to reduce their risk of atherosclerotic cardiovascular disease. [1] If triglyceride levels are persistently high, pharmacological intervention is warranted, beginning with fibrates, which are shown to lower triglyceride levels up to 70%. [11] Fenofibrate is generally preferred over gemfibrozil due to the increased risk of muscle toxicity when used together with statins. [1] In addition, according to the REDUCE-IT trial, omega-3 agents can further reduce triglyceride levels by 15% to 35%. [12] Rarely, plasmapheresis is required to treat HTG acutely. The American Society of Apheresis’ 2016 guidelines recommend the use of plasmapheresis in HTG-induced pancreatitis (Grade 2C). [13] The mechanism is such that during filtration, the passage of high molecular weight molecules such as triglycerides is prevented. [4] The evidence for this therapy is currently not substantial.

There were limitations to our patient evaluation and management. No genetic studies or additional antibody tests, such as islet antigen 2 or insulin autoantibody measurements were performed, which could have provided diagnostic evidence of type-1 DM and lipid disorders. Additionally, we could not exclude HTG triggering DKA. In vitro studies by Garg et al, [10] have shown that “high concentrations of triglyceride-rich CLDL particles may impair insulin action by inhibiting insulin binding to its receptor.” This could imply that insulin-resistance can occur secondary to hyperlipidemia.

4 Conclusion

In summary, our case represents a rare occurrence of severe HTG with DKA in an adult patient without a history of type-1 DM. This case encourages routine testing lipid panels in those with uncontrolled DM. Though evidence may be lacking, plasmapheresis was effective for this patient. Hence, this case supports the expanded use of plasmapheresis in patients with similar presentations of severe HTG.

Acknowledgments

I would like to thank my mentors for helping me finalize this report and to Paige, the medical student who helped me with the literature review.

Author contributions

Conceptualization: Pooja Roy.

Data curation: Pooja Roy.

Investigation: Paige Koetter.

Resources: Pooja Roy.

Supervision: John Cinicola.

Validation: Pooja Roy.

Visualization: Pooja Roy.

Writing – original draft: Pooja Roy.

Writing – review & editing: Pooja Roy, Jessica Cunningham, Saketram Komanduri.

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case report; diabetic ketoacidosis; plasmapheresis; severe hypertriglyceridemia

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Successful management of severe diabetic ketoacidosis in a patient with type 2 diabetes with insulin allergy: a case report

• Anh Dat Nguyen 1 , 2 ,
• Chinh Quoc Luong 1 , 2 ,
• Hieu Chi Chu 3 , 4 ,
• Van Khoa Dieu Nguyen 5 , 6 ,
• Chi Van Nguyen 1 , 2 ,
• Tuan Anh Nguyen 1 , 2 ,
• Quan Huu Nguyen 1 , 2 ,
• Ton Duy Mai 1 , 2 ,
• Dinh Van Nguyen 3 , 4 ,
• Bay Quang Nguyen 5 , 6 ,
• Thong Huu Tran 1 , 2 ,
• Phuong Viet Dao 1 , 2 ,
• Dat Tuan Nguyen 1 , 2 ,
• Nguyet Nhu Nguyen 3 , 4 &
• Son Ngoc Do   ORCID: orcid.org/0000-0001-6957-377X 1 , 2  

BMC Endocrine Disorders volume  19 , Article number:  121 ( 2019 ) Cite this article

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Diabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes that requires immediate treatment. Allergic reaction to insulin is rare, especially when using recombinant human insulin. The clinical presentation of insulin allergy can range from minor local symptoms to a severe generalized allergic reaction such as anaphylaxis. A limited number of cases have been reported on the treatment of severe DKA in patients with type 2 diabetes with insulin allergy. Here, we describe a patient with type 2 diabetes with insulin allergy in which severe DKA resolved after the initiation of continuous intravenous (IV) recombinant human insulin infusion.

Case presentation

A 58-year-old man with type 2 diabetes initiated subcutaneous insulin administration (SIA) after failure of oral antidiabetic treatment. Symptoms of an allergic reaction developed, including pruritic wheals appearing within 10 min of injection and lasting over 24 h. Both skin prick and intradermal tests were positive with different types of insulin. Two days before admission, he stopped SIA because of allergic symptoms and then experienced weakness and upper abdominal pain. On admission, he was in severe metabolic acidosis with a pH of 6.984 and bicarbonate of 2.5 mmol/litre. The blood glucose level was 20.79 mmol/litre, BUN 4.01 mmol/litre, creatinine 128 μmol/litre, and urinary ketone 11.44 mmol/litre. Over 24 h, metabolic acidosis was refractory to IV fluids, bicarbonate and potassium replacement, as well as haemodialysis. Ultimately, he received continuous IV recombinant human insulin infusion at a rate of 0.1 units/kg/hour, in combination with haemodiafiltration, and no further allergic reactions were observed. On day 5, ketonaemia and metabolic acidosis completely resolved. He had transitioned from IV insulin infusion to SIA on day 14. He was discharged on day 21 with SIA treatment. Three months later, he had good glycaemic control but still had allergic symptoms at the insulin injection sites.

Conclusions

In this patient, SIA caused an allergic reaction, in contrast to continuous IV insulin infusion for which allergic symptoms did not appear. Continuous IV recombinant human insulin infusion in combination with haemodiafiltration could be an option for the treatment of severe DKA in patients with diabetes with insulin allergy.

Peer Review reports

Diabetic ketoacidosis (DKA) is one of the most serious acute complications of diabetes that mainly occurs in patients with type 1 diabetes, but it is not uncommon in some patients with type 2 diabetes [ 1 , 2 ]. The treatment for DKA includes correction of the fluid and electrolyte abnormalities and the administration of insulin. Moreover, patients with refractory DKA may improve following treatment with continuous venovenous haemodiafiltration (CVVHDF) and appropriate supportive care [ 3 , 4 , 5 ]. Allergic reaction to insulin is rare, especially when using recombinant human insulin, with a frequency of less than 1% in patients with diabetes [ 6 ]. The clinical presentation of insulin allergy can range from minor local symptoms to a severe generalized allergic reaction, specifically anaphylaxis [ 7 , 8 ]. Insulin allergy can be managed safely and successfully by desensitization treatment [ 7 , 9 ]. However, a limited number of cases have been reported on the treatment of severe DKA in patients with type 2 diabetes with insulin allergy. Here, we describe a patient with type 2 diabetes with an insulin allergy in which severe DKA resolved after the initiation of continuous intravenous (IV) recombinant human insulin infusion in combination with haemodiafiltration.

In August 2018, a 58-year-old man [height: 169 cm, body weight: 56 kg, and body mass index (BMI): 19.6 kg/m 2 ] was admitted to our emergency department with upper abdominal pain, hyperglycaemia and metabolic acidosis. He had lived with type 2 diabetes for 16 years and had no history of any allergy, hypertension, hyperlipidaemia or renal diseases. Five months prior to admission, he initiated subcutaneous insulin administration (SIA) with the biphasic insulin analogue aspart after failure of sitagliptin and metformin therapies (HbA1c: 8.07% [65 mmol/mol]). Glycaemic control did not improve (HbA1c: 10.2% [88 mmol/mol]; total daily insulin dose was 20 UI), and aspart administration caused mild allergic symptoms. Aspart was then substituted by biphasic human insulin in which the total daily insulin dose increased up to 37 units. However, 5 months after the initiation of these regimens, he developed a pruritic wheal, especially distinct at the injection site (Fig.  1 a). Pruritic wheals appeared within 10 min of injection and lasted over 24 h. The levels of fasting blood glucose and HbA1c deteriorated to 8.6 mmol/litre and 11.2% (99 mmol/mol), respectively. An allergy to insulin was then suspected. A skin prick test was carried out with different types of insulin [insulin aspart (NovoRapid®), recombinant human insulin (Actrapid® and Insulatard®), insulin glargine (Lantus Solostar®), and insulin lispro (Humalog®, Humalog mix®)] in which the test was positive for all of these types. Two days before admission, he stopped SIA because of an allergic reaction and was treated with anti-allergic drugs.

Allergic reactions to insulin. Before admission, the allergic reaction to insulin was characterized by urticaria with wheals (some of which are confluent) and flares (erythaema) on the abdominal wall surrounding the umbilicus ( a ). Over 3 months after being discharged, the local allergic reaction to insulin presents with an erythaema and swelling at the injection site – the outer side and front of the upper right thigh ( b )

One day later, he experienced weakness and upper abdominal pain. On admission, clinical examination revealed a dehydrated patient with a heart rate (HR) of 130 beats/minute, a temperature of 37 °C and a systolic/diastolic blood pressure (BP) of 150/90 mmHg. He was tachypnoeic and dyspnoeic with a respiratory rate (RR) of 28 breaths/minute. He had hot and dry skin without pruritic wheals, isochoric pupils, and had no focal neurological deficit. He had normal breath sounds and a soft and non-tender abdomen. Electrocardiogram showed sinus tachycardia at a rate of 130 beats/minute. Echocardiography revealed normal chamber size and systolic function, without valvular lesions. Laboratory tests revealed high anion gap metabolic acidosis with an arterial blood pH of 6.984, bicarbonate of 2.5 mmol/litre and a serum anion gap (AG) of 26.4 mmol/litre. The arterial PO 2 and PCO 2 levels were 164.3 mmHg and 10.5 mmHg, respectively. Serum glucose was 20.79 mmol/litre, serum lactate was 1.5 mmol/litre, and urinary ketone was 11.44 mmol/litre. Serum potassium, sodium and chloride levels were 5.7 mmol/litre, 137.4 mmol/litre and 114.2 mmol/litre, respectively. Liver and renal function tests were normal, and there was a slightly elevated white blood cell count of 14.1 × 10 9 /l. He was admitted to our emergency ICU with a diagnosis of severe DKA in a patient with type 2 diabetes with an insulin allergy. Intravenous (IV) fluids, bicarbonate and potassium replacement and intermittent haemodialysis (IHD) were initiated. During the first 12 h, he received an initial 1 litre IV bolus of normal saline (0.9% NaCl) in the first hour, followed by a rate of 250 mL/hour, with 26 mmol of potassium chloride added per litre of normal saline. He also received 500 mL of sodium bicarbonate 1.4% solution over 2 h and then repeated as needed. However, his tachypnoea (35 breaths/minute) and metabolic acidosis persisted (arterial blood pH of 7.192, bicarbonate of 4.0 mmol/litre, PO 2 of 156.1 mmHg, PCO 2 of 10.3 mmHg, AG of 24.69 mmol/litre), prompting the initiation of CVVHDF using the Prismaflex® system (Gambro Lundia AB, Sweden) at the following settings: blood flow, 160 mL/minute; replacement volume, 1200 mL/hour; and dialysate, 1200 mL/hour. After 24 h of fluid resuscitation (6500 mL), he was haemodynamically stable and had 3500 mL of urinary output. However, he developed a decreased level of consciousness, agitation, and fatigue of his respiratory muscles. He was intubated for airway protection and was mechanically ventilated for respiratory support. Furthermore, hypotension (HR and BP were 120 beats/minute and 80/40 mmHg, respectively) occurred after intubation. A bolus of normal saline (1000 mL) was provided, and norepinephrine was administered at a rate of 0.3 μg/kg/minute. Haemodynamic stability was recovered after 1 h, with a HR of 110 beats/minute, BP of 120/60 mmHg, and measured CVP value of 8 cmH 2 O. Arterial blood gases revealed a worsening metabolic acidosis with an arterial blood pH of 7.022, bicarbonate of 2.5 mmol/litre and a serum AG of 25.75 mmol/litre. Renal function declined with a serum creatinine level of 198 μmol/litre. Serum glucose, potassium, sodium and chloride levels were 23.32 mmol/litre, 4.35 mmol/litre, 140.5 mmol/litre and 116.6 mmol/litre, respectively. CVVHDF and IV fluids and potassium replacement were continued. Although haemodynamic and respiratory stabilities were maintained, metabolic acidosis persisted. Further skin prick testing with different types of insulin [insulin aspart (NovoRapid®), recombinant human insulin (Actrapid®, Insulatard®, Mixtard®, Humulin R®, and Humulin N®), and insulin glargine (Lantus®)] only showed positivity to two (aspart, human) of these types. However, the intradermal test with these types was positive (the time of testing as shown in Additional file 1 ). A 40 mg dose of methylprednisolone sodium succinate and 10 mg of diphenhydramine were given in the event of the possible occurrence of a severe allergic reaction, and continuous IV infusion of recombinant human insulin was initiated at a rate of 0.1 units/kg/hour. Approximately 60 min after continuous IV infusion of insulin, he developed hypotension without any signs or symptoms of allergic reactions of the skin and mucosa, and the HR was 115 beats/minute and BP was 80/40 mmHg. Infusion of insulin was temporarily stopped followed by intravenous epinephrine administration at a starting rate of 0.15 μg/kg/minute in addition to an IV bolus of 1000 mL of normal saline. He regained haemodynamic stability after 30 min, including a HR of 110 beats/minute and a BP of 120/70 mmHg, and did not require any additional administration of epinephrine after 5 h. Continuous IV infusion of recombinant human insulin at a rate of 0.1 units/kg/hour continued without any events such as signs or symptoms of allergic reactions and hypotension.

On day 5 of follow-up, ketonaemia, metabolic acidosis (arterial blood pH of 7.465, bicarbonate of 18.4 mmol/litre and AG of 12.73 mmol/litre), and renal dysfunction (serum creatinine of 108 μmol/litre) had almost resolved, and CVVHDF was withdrawn. He did not require vasoconstrictors. Continuous IV infusion of recombinant human insulin continued and was adjusted according to blood glucose levels measured with a portable blood glucose meter. He was extubated on day 7 and transitioned from continuous IV insulin infusion to subcutaneous insulin (combined regular human insulin with insulin glargine) administration on day 14. He was discharged on day 21 with SIA (combined regular human insulin with insulin glargine) in combination with an oral antidiabetic drug (sitagliptin and metformin). Three months later, glycaemic control was gradually restored (HbA1c: 8.3% [67 mmol/mol]; total daily insulin dose was up to 44 UI); he still appeared to have mild allergic symptoms, such as local erythaema and swelling, especially distinct at the injection site of insulin glargine (Fig. 1 b).

Discussion and conclusions

DKA is not just the hallmark of absolute insulin deficiency in type 1 diabetes; it is increasingly being seen in people presenting with type 2 diabetes [ 2 ]. This condition is a complex disordered metabolic state characterized by hyperglycaemia, high anion gap metabolic acidosis, and ketonuria [ 10 ]. DKA must be distinguished from other causes of high anion gap metabolic acidosis, including lactic acidosis (which can rarely be associated with metformin), aspirin or acetaminophen toxicity and poisoning with methanol, ethylene glycol, and propylene glycol [ 10 , 11 ]. The clinical and laboratory findings of our patient, however, revealed a typical DKA according to the diagnostic criteria proposed by the American Diabetes Association (ADA) [ 10 ]. DKA is an acute, major, life-threatening complication of diabetes that requires immediate treatment. Although DKA has a low rate of hospital mortality, the short-term risk of death is associated with recurrent DKA admissions in patients with diabetes [ 12 ]. However, this disorder can have significant mortality if misdiagnosed or mistreated, which is almost 100% without insulin therapy [ 13 ].

Over the first 30 h after admission, our patient was managed following the ADA guidelines for the treatment of hyperglycaemic crises in adult patients with diabetes [ 10 ], except for the administration of insulin. During this period of time, he also received IHD and CVVHDF for correcting severe DKA, but it persisted. The correction of metabolic acidosis with bicarbonate administration in the treatment of patients with DKA is controversial [ 14 ]. On rare occasions, IHD may be required to treat metabolic acidosis associated with renal failure. Combined CVVHDF with continuous IV insulin infusion was previously performed to treat successfully patients with refractory DKA [ 3 , 5 ]. It is hypothesised that CVVHDF has a role in removal of plasma growth hormone (GH) and insulin growth factor 1 (IGF-1), similar to the clearance of other medium size molecules such as brain natriuretic peptide and procalcitonin [ 4 ]. In our patient, severe DKA was refractory to IHD, and duration of CVVHDF before initiation of continuous IV recombinant human insulin infusion was too short to draw conclusion dealing with clinical effect of CVVHDF in combination with other appropriate supportive care on the treatment of severe DKA. However, severe DKA in our patient resolved over a few days after starting combined CVVHDF with continuous IV recombinant human insulin infusion.

Immediate reactions to insulin preparations are believed to be immunoglobulin (Ig) E-mediated, type I immunologic reactions to insulin or to an additive [ 15 ]. The insulin-IgE complex binds to IgE receptors on the surface of basophils and mast cells, causing release of inflammatory mediators such as histamine, resulting in the minor local to severe generalized allergic reaction [ 16 ]. The IgE and IgG immunoassays were not available at our hospital; therefore, the patient was not assessed. However, his clinical features and skin tests showed a typical type-I allergic reaction according to the Gell and Coombs classification [ 17 ]. Anaphylaxis is the most severe presentation of an IgE-mediated drug reaction, and the skin and/or mucous membranes are involved in almost all cases [ 18 ]. In our patient, hypotension developed both before and after beginning continuous IV recombinant human insulin infusion, as well as after intubation without any signs or symptoms of allergic reactions of the skin and mucous membranes. However, his haemodynamic stabilities were rapidly obtained after adequate IV fluid replacement, and he did not require any further administration of epinephrine. Three risk factors for post-intubation hypotension were identified by multivariate analysis: decreasing mean arterial pressure pre-intubation, administration of neuromuscular blockers, and intubation complications [ 19 ]. In our patient, hypotension could therefore be attributed to decreasing mean arterial pressure pre-intubation and/or administration of neuromuscular blockers rather than severe allergic reactions.

Insulin allergy can be managed safely and successfully by desensitization treatment with the subcutaneous insulin route [ 7 , 9 , 20 ]. However, insulin tolerability in a severely insulin-allergic patient with diabetes could also be achieved by the use of intravenously injected insulin [ 21 ]. In this patient, treatment attempts of specific immunotherapy with subcutaneous administration of insulin, with continuous subcutaneous injection of insulin lispro, and with oral anti-allergic agents did not prevent frequent life-threatening allergic symptoms, especially after bolus injections with meals. Ultimately, no allergic reactions were observed after the authors applied the required insulin intravenously over a central line at a dose of 100 UI per 500 mL with a portable pump delivering 5–10 mL/hour, adjusted according to self-monitored blood glucose levels [ 21 ]. In our patient, severe DKA was refractory to IV fluid and sodium bicarbonate therapies and IHD. However, DKA resolved within several days after beginning continuous IV recombinant regular human insulin infusion in combination with CVVHDF, and no allergic symptoms were observed as previously described. Moreover, our patient appeared allergic symptoms with subcutaneous administration of insulin after transitioning from continuous IV insulin infusion. This phenomenon was also observed in the patient earlier, of whom the levels of anti-human insulin IgE although returned to normal, as did the levels of anti-human insulin IgG bound/total, without any adverse effect on glucose control, subcutaneous injection of regular insulin still caused immediate allergic reactions [ 21 ]. A previous study found that insulin treatment led to the production of antibodies against insulin [ 22 ]. A literature review had shown that the development of insulin antibodies was initially thought to be due to slight immunogenicity induced by the refining of preparations or the difference in amino acid sequences between species. When genetically engineered preparations of human insulin, however, are used, anti-human insulin IgG subclasses still are frequently detected in patients treated with insulin [ 23 ]. Thus, identical insulin molecules can behave in markedly different ways depending on the route of injection. Additionally, it is possible that the formation of anti-human insulin IgG is caused only by insulin molecules that are in contact with subcutaneous tissue [ 21 ]. These were assumed that some modification of insulin, such as aggregation, leads to the immunologic reactions [ 21 , 24 , 25 ].

In our patient, SIA caused an allergic reaction, in contrast to continuous IV insulin infusion, for which allergic symptoms did not appear. We believe that the presentation and progression of our patient indicated that continuous IV recombinant human insulin infusion in combination with haemodiafiltration could be an option for the treatment of severe DKA in patients with diabetes with insulin allergy.

Availability of data and materials

Not applicable.

Abbreviations

American Diabetes Association

Blood pressure

Blood urea nitrogen

Central venous pressure

Continuous venovenous haemodiafiltration

• Diabetic ketoacidosis

Intensive care unit

Immunoglobulin

Intermittent hemodialysis

Intravenous

Partial pressure of carbon dioxide

Partial pressure of oxygen

Respiratory rate

Subcutaneous insulin administration

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Acknowledgements

We thank the patient, his family and the medical staff who cared for him. We thank Associate Professor Bryan Francis McNally, MD, MPH, from the Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA for his support with our manuscript.

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Department of Emergency and Critical Care Medicine, Hanoi Medical University, 01 Ton That Tung street, Kim Lien ward, Dong Da district, Hanoi, Vietnam

Anh Dat Nguyen, Chinh Quoc Luong, Chi Van Nguyen, Tuan Anh Nguyen, Quan Huu Nguyen, Ton Duy Mai, Thong Huu Tran, Phuong Viet Dao, Dat Tuan Nguyen & Son Ngoc Do

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Allerology and Clinical Immunology Center, Bach Mai Hospital, 78 Giai Phong road, Phuong Mai ward, Dong Da district, Hanoi, Vietnam

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CQL wrote the manuscript, researched the data, and contributed to the discussion. ADN contributed to the discussion and reviewed/edited the manuscript. HCC contributed to the discussion. VKDN contributed to the discussion. CVN contributed to the discussion. TAN contributed to the discussion. QHN contributed to the discussion. TDM contributed to the discussion. DVN contributed to the discussion. BQN researched the data and contributed to the discussion. THT contributed to the discussion. PVD researched the data. DTN researched the data. NNN researched the data. SND contributed to the discussion and reviewed/edited the manuscript. All authors approved the final version of the manuscript. Guarantor: CQL.

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Nguyen, A.D., Luong, C.Q., Chu, H.C. et al. Successful management of severe diabetic ketoacidosis in a patient with type 2 diabetes with insulin allergy: a case report. BMC Endocr Disord 19 , 121 (2019). https://doi.org/10.1186/s12902-019-0451-7

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On March 6th, 2019, Maria Fernandez, a 19-year-old female, presented to the Emergency Department with complaints of nausea, vomiting, abdominal pain, and lethargy. She reveals a recent diagnosis of type 1 diabetes but admits to noncompliance with treatment. At the time of admission, Maria’s vital signs were as follows: BP 87/50, HR 118, RR 28, O2 95% on room air, diffuse abdominal pain at a level of 5, on a verbal numeric 1-10 scale, with non-radiating pain beginning that morning. She was A&O x3, oriented to self, place, and situation, but sluggish. Upon assessment it is revealed that she is experiencing blurry vision, Kussmaul respirations, dry, flushed skin, poor skin turgor, weakness, and a fruity breath smell. Labs were drawn. During the first hour of admission, Maria requested water four times and urinated three times.

Code status:  Full code

Medical hx : Type 1 Diabetes

Insurance : None

Allergies : NKA

Significant Lab Values

• Blood glucose 388
• ABGs: pH 7.25, Bicarb 12 mEq/L, paCO2 30 mm Hg, anion gap 20 mEq/L, paO2 94%
• Urinalysis: Ketones and acetone present, BUN 25 mL/dL, Cr 2.1 ml/dL
• Chemistry: sodium 111 mEq/L, potassium 5.5 mEq/L, chloride 90 mEq/L, phosphorus 2.5 mg/dL, Magnesium 2.0 mg/dL
• CBC: WBC 13,000 mcL, RBC 4.7 mcL, Hgb 12.6 g/dL , Hct 37% (Wolters Kluwer, 2018).

Diagnosis:  Diabetes Ketoacidosis

• Oxygen administration by nasal cannula on 2L and airway management
• Establish IV access
• IV fluid administration with 0.9% NS; prepare to titrate to 0.45% normal saline as needed
• Monitor blood glucose levels
• Administer 0.1-0.15 unit/kg IV bolus of regular insulin
• IV drip infusion at 0.1 unit/kg/hr of regular insulin to hyperglycemia after bolus,
• Addition of Dextrose to 0.9% NS as glucose levels decreases to 250 mg/dL
• Monitor potassium levels
• Potassium replacement via IV when the potassium level is 5.0 mg/dL or less and urine output is adequate
• Assess for signs of hypokalemia or hyperkalemia
• Monitor vital signs and cardiac rhythm
• Q1-2hr fingerstick blood glucose checks initially, then q4-6hr once stabilized
• Monitor blood pH, I&O
• Assess level of consciousness; provide seizure and safety precautions (Henry et al., 2016)
• Notify MD of any critical changes

Maria Fernandez was then transferred to the ICU unit for close observation, maintenance of IV insulin drip, cardiac monitoring, fluid resuscitation, and correction for metabolic acidosis.

Upon discharge, Maria was reeducated on Type 1 Diabetes Mellitus through the use of preferred learning materials.

• What is the priority assessment data that supports DKA diagnosis?
• What education strategies would you consider implementing to improve treatment adherence after discharge?
• What considerations, services, or resources would you anticipate to be offered by case management or social services?

Henry, N.J., McMichael, M., Johnson, J., DiStasi, A., Ball, B.S., Holman, H.C., Elkins, C.B., Janowski, M.J., Hertel, R.A., Barlow, M.S., Leehy, P., & Lemon, T. (2016).  RN adult medical surgical nursing: Review module  (10 th  ed.). Leawood, KS: Assessment Technologies Institute.

Wolters Kluwer. (2018). Lippincott Nursing Advisor (Version 4.1.0) [Mobile application software]. Retrieved from  http://itunes.apple.com

Nursing Case Studies by and for Student Nurses Copyright © by jaimehannans is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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DYANNE P. WESTERBERG, DO

This is a corrected version of the article that appeared in print.

Am Fam Physician. 2013;87(5):337-346

Patient Information: A handout on this topic is available at https://familydoctor.org/familydoctor/en/diseases-conditions/diabetic-ketoacidosis.html .

Author disclosure: No relevant financial affiliations.

Diabetic ketoacidosis is characterized by a serum glucose level greater than 250 mg per dL, a pH less than 7.3, a serum bicarbonate level less than 18 mEq per L, an elevated serum ketone level, and dehydration. Insulin deficiency is the main precipitating factor. Diabetic ketoacidosis can occur in persons of all ages, with 14 percent of cases occurring in persons older than 70 years, 23 percent in persons 51 to 70 years of age, 27 percent in persons 30 to 50 years of age, and 36 percent in persons younger than 30 years. The case fatality rate is 1 to 5 percent. About one-third of all cases are in persons without a history of diabetes mellitus. Common symptoms include polyuria with polydipsia (98 percent), weight loss (81 percent), fatigue (62 percent), dyspnea (57 percent), vomiting (46 percent), preceding febrile illness (40 percent), abdominal pain (32 percent), and polyphagia (23 percent). Measurement of A1C, blood urea nitrogen, creatinine, serum glucose, electrolytes, pH, and serum ketones; complete blood count; urinalysis; electrocardiography; and calculation of anion gap and osmolar gap can differentiate diabetic ketoacidosis from hyperosmolar hyperglycemic state, gastroenteritis, starvation ketosis, and other metabolic syndromes, and can assist in diagnosing comorbid conditions. Appropriate treatment includes administering intravenous fluids and insulin, and monitoring glucose and electrolyte levels. Cerebral edema is a rare but severe complication that occurs predominantly in children. Physicians should recognize the signs of diabetic ketoacidosis for prompt diagnosis, and identify early symptoms to prevent it. Patient education should include information on how to adjust insulin during times of illness and how to monitor glucose and ketone levels, as well as information on the importance of medication compliance.

Diabetic ketoacidosis (DKA) continues to have high rates of morbidity and mortality despite advances in the treatment of diabetes mellitus. In a study of 4,807 episodes of DKA, 14 percent occurred in persons older than 70 years, 23 percent in persons 51 to 70 years of age, 27 percent in persons 30 to 50 years of age, and 36 percent in persons younger than 30 years. 1 In a second study of 28,770 persons younger than 20 years (mean age of 14 years) with diabetes, 94 percent had no episodes of DKA, 5 percent had one episode, and 1 percent had at least two episodes. 2 Additionally, DKA occurred more often in females, in persons with a migration background, and in persons 11 to 15 years of age. 2 DKA has a case fatality rate of 1 to 5 percent. 3 , 4 Although the highest rate of mortality is in older adults and persons with comorbid conditions, DKA is the leading cause of death in persons younger than 24 years with diabetes, most often because of cerebral edema. 1 , 4

Although persons with DKA typically have a history of diabetes, 27 to 37 percent have newly diagnosed diabetes. 5 , 6 This is especially true in young children. Most persons with DKA have type 1 diabetes. There is also a subgroup of persons with type 2 diabetes who have ketosis-prone diabetes; this subgroup represents 20 to 50 percent of persons with DKA. 7 Persons with ketosis-prone diabetes have impaired insulin secretion; however, with proper glucose management, beta cell function improves and the clinical course resembles that of type 2 diabetes. 8 These persons are often black or Latino, male, middle-aged, overweight or obese, have a family history of diabetes, and have newly diagnosed diabetes. 9

Pathophysiology

DKA results from insulin deficiency from new-onset diabetes, insulin noncompliance, prescription or illicit drug use, and increased insulin need because of infection ( Table 1 ) . 4 , 10 – 16 This insulin deficiency stimulates the elevation of the counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Without the ability to use glucose, the body needs alternative energy sources. Lipase activity increases, causing a breakdown of adipose tissue that yields free fatty acids. These components are converted to acetyl coenzyme A, some of which enter the Krebs cycle for energy production; the remainder are broken down into ketones (acetone, acetoacetate, and β-hydroxybutyrate). Ketones can be used for energy, but accumulate rapidly. Glycogen and proteins are catabolized to form glucose. Together, these factors promote hyperglycemia, which leads to an osmotic diuresis resulting in dehydration, metabolic acidosis, and a hyperosmolar state ( eFigure A ) .

TYPICAL CLINICAL PRESENTATION

The presentation of DKA varies with severity and comorbid conditions. Polyuria with polydipsia is the most common presenting symptom and was found in 98 percent of persons in one study of childhood type 1 diabetes. Other common symptoms included weight loss (81 percent), fatigue (62 percent), dyspnea (57 percent), vomiting (46 percent), preceding febrile illness (40 percent), abdominal pain (32 percent), and polyphagia (23 percent). 17 Dehydration causes tachycardia, poor skin turgor, dry mucous membranes, and orthostatic hypotension. The metabolic acidosis may lead to compensatory deep (Kussmaul) respirations, whereas increased acetone can be sensed as a fruity smell on the patient's breath. Mental status can vary from somnolence to lethargy and coma. A detailed evaluation may reveal precipitating factors, especially nonadherence to medical regimens and infection, which are common causes of DKA.

DIFFERENTIAL DIAGNOSIS

Although hyperosmolar hyperglycemic state can be confused with DKA, ketone levels are low or absent in persons with hyperosmolar hyperglycemic state. Other causes of high anion gap metabolic acidosis, such as alcoholic ketoacidosis and lactic acidosis, must be ruled out. Table 2 provides the differential diagnosis of DKA. 14 , 18

DIAGNOSTIC TESTING

The diagnosis of DKA ( Table 3 ) is based on an elevated serum glucose level (greater than 250 mg per dL [13.88 mmol per L]), an elevated serum ketone level, a pH less than 7.3, and a serum bicarbonate level less than 18 mEq per L (18 mmol per L). 4 Although arterial blood gas measurement remains the most widely recommended test for determining pH, measurement of venous blood gas has gained acceptance. One review indicated that venous and arterial pH are clinically interchangeable in persons who are hemodynamically stable and without respiratory failure. 19 Traditionally, the severity of DKA is determined by the arterial pH, bicarbonate level, anion gap, and mental status of the patient ( Table 3 ) . 4 An anion gap greater than 16 mEq per L (16 mmol per L) confirms metabolic acidosis. Although persons with DKA usually have a glucose level greater than 250 mg per dL, a few case reports document DKA in pregnant women who were euglycemic. 20 , 21 Persons with hyperglycemia have pseudohyponatremia, and serum sodium concentration should be corrected. Table 4 provides formulas to calculate the anion gap, serum osmolality, osmolar gap, and serum sodium correction. 16 [ corrected ]

Urinalysis measures only acetone and acetoacetate, not β-hydroxybutyrate, which is the primary ketone in DKA. In one study, the urine dipstick test was negative for ketones in six of 18 persons. Ketonemia was defined as a ketone level greater than 0.42 mmol per L. 22 In a second study of point-of-care testing in the emergency department, urine dipstick testing for ketones had a sensitivity of 98 percent, specificity of 35 percent, and a positive predictive value of 15 percent. Serum testing for β-hydroxybutyrate had a sensitivity of 98 percent, a specificity of 79 percent, and a positive predictive value of 34 percent (using a cutoff of greater than 1.5 mmol per L), allowing for more accurate diagnosis of DKA. 23 The American Diabetes Association has revised its position on ketone analysis in favor of serum testing, and has concluded that capillary measurement is equivalent to venous measurement. 4 , 22 , 24

Further initial laboratory studies should include measurement of electrolytes, phosphate, blood urea nitrogen, and creatinine; urinalysis; complete blood count with differential; and electrocardiography ( Table 5 ) . 16 Potassium level is normal or low in persons with DKA, despite renal losses caused by the acidic environment. An initial potassium level less than 3.3 mEq per L (3.3 mmol per L) indicates profound hypokalemia. Amylase and lipase levels may be increased in persons with DKA, even in those without associated pancreatitis; however, 10 to 15 percent of persons with DKA do have concomitant pancreatitis. 18 , 25

Leukocytosis can occur even in the absence of infection; bandemia more accurately predicts infection. One study showed that an elevated band count in persons with DKA had a sensitivity for predicting infection of 100 percent (19 out of 19 cases) and a specificity of 80 percent. 26 Chest radiography and urine and blood cultures should be added for further evaluation of infection. An elevated hemoglobin level caused by dehydration may also exist. Elevated hepatic transaminase levels may occur, especially in persons with fatty liver disease. 27 Mild increases in creatine kinase and troponin levels may occur in the absence of myocardial damage; one study demonstrated that increased troponin levels occurred in 26 out of 96 persons with DKA without a coronary event. 28 Finally, the A1C level indicates the degree of glycemic control in persons known to have diabetes.

Figure 1 4 , 29 provides the treatment approach for DKA in adults, and Figure 2 24 , 30 provides the treatment approach for DKA in persons younger than 20 years. Both approaches are recommended by the American Diabetes Association. Specific issues for the adult patient are discussed in more detail below. For persons younger than 20 years, insulin should be administered gradually, and fluid and electrolyte replacement should be done cautiously because of limited data and concern for precipitating cerebral edema.

FLUID REPLACEMENT

After determining the level of dehydration, intravenous fluid replacement should be started. In most persons, saline 0.9% is started at 15 to 20 mL per kg per hour, or 1 L per hour initially. Fluid status, cardiac status, urine output, blood pressure, and electrolyte level should be monitored. As the patient stabilizes, fluids can be lowered to 4 to 14 mL per kg per hour, or 250 to 500 mL per hour. Once the corrected sodium concentration is normal or high (greater than 135 mEq per L [135 mmol per L]), the solution can be changed to saline 0.45%. Dextrose is added when the glucose level decreases to 200 mg per dL (11.10 mmol per L). 4

To further correct hyperglycemia, insulin should be added to intravenous fluids one to two hours after fluids are initiated. An initial bolus of 0.1 units per kg should be given with an infusion of 0.1 units per kg per hour. 4 Some believe this bolus is unnecessary as long as an adequate infusion of insulin is maintained. 31 An infusion of 0.14 units per kg per hour is recommended in the absence of a bolus. Glucose level should decrease by about 50 to 70 mg per dL (2.77 to 3.89 mmol per L) per hour, and the insulin infusion should be adjusted to achieve this goal. 4 Once the glucose level decreases to 200 mg per dL, the insulin infusion rate should be decreased to 0.05 to 0.1 units per kg per hour, and dextrose should be added to the intravenous fluids to maintain a glucose level between 150 and 200 mg per dL (8.32 and 11.10 mmol per L). 4 Subcutaneous insulin is an effective alternative to intravenous insulin in persons with uncomplicated DKA. 29 In one prospective randomized trial of 45 persons, 15 received insulin aspart (Novolog) hourly, 15 received insulin aspart every two hours, and 15 received standard intravenous infusion of regular insulin. Physiologic and clinical outcomes were identical in all three groups. 32 A meta-analysis supports subcutaneous administration of rapid-acting insulin analogues, such as lispro (Humalog), every hour (bolus of 0.3 units per kg, then 0.1 units per kg) or two hours (bolus of 0.3 units per kg, then 0.2 units per kg) as a reasonable alternative to intravenous regular insulin for treating uncomplicated DKA. 29

DKA is resolved when the glucose level is less than 200 mg per dL, the pH is greater than 7.3, and the bicarbonate level is 18 mEq per L or higher. 4

Once these levels are achieved and oral fluids are tolerated, the patient can be started on an insulin regimen that includes an intermediate- or long-acting insulin and a short- or rapid-acting insulin. When intravenous insulin is used, it should remain in place for one to two hours after subcutaneous insulin is initiated. Persons known to have diabetes can be started on their outpatient dose, with adjustments to improve control. Those new to insulin should receive 0.5 to 0.8 mg per kg per day in divided doses. 4

Although potassium is profoundly depleted in persons with DKA, decreased insulin levels, acidosis, and volume depletion cause elevated extracellular concentrations. Potassium levels should be monitored every two to four hours in the early stages of DKA. Hydration alone will cause potassium to drop because of dilution. Improved renal perfusion will increase excretion. Insulin therapy and correction of acidosis will cause cellular uptake of potassium. If the potassium level is in the normal range, replacement can start at 10 to 15 mEq potassium per hour. During treatment of DKA, the goal is to maintain serum potassium levels between 4 and 5 mEq per L (4 and 5 mmol per L). If the potassium level is between 3.3 and 5.2 mEq per L (3.3 and 5.2 mmol per L) and urine output is normal, replacement can start at 20 to 30 mEq potassium per hour. If the potassium level is lower than 3.3 mEq per L, insulin should be held and replacement should be started at 20 to 30 mEq potassium per hour. If the potassium level is greater than 5.2 mEq per L, insulin therapy without potassium replacement should be initiated, and serum potassium levels should be checked every two hours. When the potassium level is between 3.3 and 5.2 mEq per L, potassium replacement should be initiated. 4 Some guidelines recommend potassium replacement with potassium chloride, whereas others recommend combining it with potassium phosphate or potassium acetate. Clinical trials are lacking to determine which is best, although in the face of phosphate depletion, potassium phosphate is used.

BICARBONATE

Bicarbonate therapy in persons with DKA is somewhat controversial. Proponents believe that severe acidosis will cause cardiac and neurologic complications. However, studies have not demonstrated improved clinical outcomes with bicarbonate therapy, and treatment has been associated with hypokalemia. In one retrospective quasi-experimental study of 39 persons with DKA and a pH between 6.9 and 7.1, there was no difference in outcomes between those who received bicarbonate therapy and those who did not. 33 A second study of 106 adolescents with DKA showed no difference in outcomes in patients treated with and without sodium bicarbonate, but few had a pH below 7 and only one had a pH below 6.9. 34

Current American Diabetes Association guidelines continue to recommend bicarbonate replacement in persons with a pH lower than 6.9 using 100 mEq of sodium bicarbonate in 400 mL of sterile water with 20 mEq of potassium chloride at a rate of 200 mL per hour for two hours. This should be repeated every two hours until the patient's pH is 6.9 or greater. 4

PHOSPHATE AND MAGNESIUM

Phosphate levels may be normal to elevated on presentation, but decline with treatment as the phosphate enters the intracellular space. Studies have not shown a benefit from phosphate replacement, and it can be associated with hypocalcemia and hypomagnesemia. However, because phosphate deficiency is linked with muscle fatigue, rhabdomyolysis, hemolysis, respiratory failure, and cardiac arrhythmia, replacement is recommended when the phosphate level falls below 1.0 mg per dL (0.32 mmol per L) or when these complications occur. 4 Persons with anemia or respiratory problems and congestive heart failure may benefit from phosphate. This can be achieved by adding 20 to 30 mEq of potassium phosphate to the intravenous fluid. 4

DKA can cause a drop in magnesium, which can result in paresthesia, tremor, muscle spasm, seizures, and cardiac arrhythmia. It should be replaced if it falls below 1.2 mg per dL or if symptoms of hypomagnesemia develop. 35

Complications

Cerebral edema is the most severe complication of DKA. It occurs in 0.5 to 1 percent of all DKA cases, 36 , 37 and carries a mortality rate of 21 to 24 percent. 30 Survivors are at risk of residual neurologic problems. 38 Cerebral edema predominantly occurs in children, although it has been reported in adults. 39 Risk factors include younger age, new-onset diabetes, longer duration of symptoms, lower partial pressure of carbon dioxide, severe acidosis, low initial bicarbonate level, low sodium level, high glucose level at presentation, rapid hydration, and retained fluid in the stomach. 30 , 40 Signs of cerebral edema that require immediate evaluation include headache, persistent vomiting, hypertension, bradycardia, and lethargy and other neurologic changes.

Other complications of DKA include hypokalemia, hypoglycemia, acute renal failure, and shock. Less common problems can include rhabdomyolysis, 41 thrombosis and stroke, 42 pneumomediastinum, 43 prolonged corrected QT interval, 44 pulmonary edema, 45 and memory loss with decreased cognitive function in children. 46

Physicians should recognize signs of diabetes in all age groups, and should educate patients and caregivers on how to recognize them as well ( eTable A ) . In one study, persons with DKA had symptoms of diabetes for 24.5 days before developing DKA. 17 Persons with diabetes and their caregivers should be familiar with adjusting insulin during times of illness. This includes more frequent glucose monitoring; continuing insulin, but at lower doses, during times of decreased food intake; and checking urine ketone levels with a dipstick test if the glucose level is greater than 240 mg per dL (13.32 mmol per L). 47 More accessible home measurement of serum ketones with a commercial glucometer may allow for earlier detection of DKA and decreased hospital visits. 48 Persons with an insulin pump need to know their pump settings, and should maintain a prescription for basal insulin in case of pump failure.

Nonadherence to medical regimens is often the cause of recurrent DKA. Physicians need to recognize patient barriers to getting care, such as financial, social, psychological, and cultural reasons. Diabetes education with certified educators and pharmacists enhances patient care. 49 , 50 Other prevention techniques include group visits, telecommunication, web-based learning, and copay reduction for diabetes medications; however, evidence for their effectiveness is mixed. 51 – 55

Data Sources: In July 2010, an initially broad search of PubMed, Essential Evidence Plus, and sources such as the Cochrane database and Clinical Evidence was conducted using the key term diabetic ketoacidosis. In the fall of 2010, another search was conducted using additional key terms, such as incidence and prevalence. As information was collected, individual questions were then searched to add finer points to the documentation. The searches were repeated with each draft of the manuscript.

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Yadav D, Nair S, Norkus EP, Pitchumoni CS. Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol. 2000;95(11):3123-3128.

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Takaike H, Uchigata Y, Iwamoto Y, et al. Nationwide survey to compare the prevalence of transient elevation of liver transaminase during treatment of diabetic ketosis or ketoacidosis in new-onset acute and fulminant type 1 diabetes mellitus. Ann Med. 2008;40(5):395-400.

Al-Mallah M, Zuberi O, Arida M, Kim HE. Positive troponin in diabetic ketoacidosis without evident acute coronary syndrome predicts adverse cardiac events. Clin Cardiol. 2008;31(2):67-71.

Mazer M, Chen E. Is subcutaneous administration of rapid-acting insulin as effective as intravenous insulin for treating diabetic ketoacidosis?. Ann Emerg Med. 2009;53(2):259-263.

Wolfsdorf J, Craig ME, Daneman D, et al. Diabetic ketoacidosis in children and adolescents with diabetes. Pediatr Diabetes. 2009;10(suppl 12):118-133.

Kitabchi AE, Murphy MB, Spencer J, Matteri R, Karas J. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis?. Diabetes Care. 2008;31(11):2081-2085.

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Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis?. Crit Care Med. 1999;27(12):2690-2693.

Green SM, Rothrock SG, Ho JD, et al. Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. 1998;31(1):41-48.

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Lawrence SE, Cummings EA, Gaboury I, Daneman D. Population-based study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis. J Pediatr. 2005;146(5):688-692.

Glaser N. Cerebral edema in children with diabetic ketoacidosis. Curr Diab Rep. 2001;1(1):41-46.

Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child. 2004;89(2):188-194.

Haringhuizen A, Tjan DH, Grool A, van Vugt R, van Zante AR. Fatal cerebral oedema in adult diabetic ketoacidosis. Neth J Med. 2010;68(1):35-37.

Carlotti AP, St George-Hyslop C, Guerguerian AM, Bohn D, Kamel KS, Halperin M. Occult risk factor for the development of cerebral edema in children with diabetic ketoacidosis: possible role for stomach emptying. Pediatr Diabetes. 2009;10(8):523-533.

Casteels K, Beckers D, Wouters C, Van Geet C. Rhabdomyolysis in diabetic ketoacidosis. Pediatr Diabetes. 2003;4(1):29-31.

Carl GF, Hoffman WH, Passmore GG, et al. Diabetic ketoacidosis promotes a prothrombotic state. Endocr Res. 2003;29(1):73-82.

Weathers LS, Brooks WG, DeClue TJ. Spontaneous pneumomediastinum in a patient with diabetic ketoacidosis: a potentially hidden complication. South Med J. 1995;88(4):483-484.

Kuppermann N, Park J, Glatter K, Marcin JP, Glaser NS. Prolonged QT interval corrected for heart rate during diabetic ketoacidosis in children. Arch Pediatr Adolesc Med. 2008;162(6):544-549.

Young MC. Simultaneous acute cerebral and pulmonary edema complicating diabetic ketoacidosis. Diabetes Care. 1995;18(9):1288-1290.

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Funnell MM, Brown TL, Childs BP, et al. National standards for diabetes self-management education. Diabetes Care. 2010;33(suppl 1):S89-S96.

Taveira TH, Friedmann PD, Cohen LB, et al. Pharmacist-led group medical appointment model in type 2 diabetes. Diabetes Educ. 2010;36(1):109-117.

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EM ReSCu Peds 5: Diabetic Ketoacidosis

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Presentation

Brief narrative description of case.

The patient’s parents brought her in for vomiting, and “tiredness.” The whole family has had the flu for the past week and all three children were home from school with fever, myalgias, diarrhea. She had a negative COVID-19 swab at a community testing site yesterday. Her siblings seem to be feeling better, but she hasn’t improved yet. She is somnolent, ill-appearing, and severely dehydrated. She is in early hypotensive shock with poor perfusion. Intravenous access attempts will be minimally effective (22g only x 1). She is hyperglycemic, and there is difficulty obtaining additional vascular access. She is hypokalemic (DKA plus diarrhea) and acidotic, which should prompt recognition of DKA with complications.

Management will require IV access (IO), appropriate fluid resuscitation, insulin drip, potassium replacement and admission/transfer.

Download the Case Summary

• What are case summaries? [PDF]
• Quick reference guide for the case  [PDF]

Primary Learning Objectives

At the end of this simulation, participants should be able to:

Describe signs/symptoms of shock in a child (comprehension)

Demonstrate early evaluation of a critically ill patient (application).

• Interpret signs/symptoms of DKA including hyperglycemia and acidosis (evaluation)

Construct and implement an initial management plan for a child in DKA (application)

Consider risks of aggressive fluid administration in the setting of dka such as cerebral edema (evaluation).

• Manage hypokalemia and hyperglycemia in the setting of insulin administration (application)

Demonstrate focused history taking from a caregiver (application)

Effectively communicate diagnosis and management to caregivers and respond appropriately to their concerns (synthesis), demonstrate teamwork and closed loop communication (application), critical actions.

• Assign/assume team roles
• Obtain brief history from parent
• Place patient on continuous cardiac monitor
• Obtain a point of care glucose
• Establish vascular access – consider IO or ultrasound guided peripheral IV (USGPIV)
• Obtain a venous/capillary blood gas to establish electrolytes/pH level
• Perform focused physical exam/primary survey
• Verbalize diagnosis of DKA
• Initiate appropriate fluid resuscitation for severe DKA
• Initiate appropriate medications (insulin, potassium)
• Communicate effectively with PICU +/- Endocrine consultants
• Explain diagnosis to parent(s) and how it relates to the patient’s presentation
• Effectively manage anxious family members

Case Creators

• Kimberly Schertzer, MD, FACEP
• Melissa Hersh, MD
• Ilana Bank, MDCM, FRCPC, FAAP
• Rebekah Burns, MD
• Sherri Rudlinsky, MD
• Josh Davis, MD, NASM-CPT
• Myto Duong, MD

Updated March 29, 2023

Chief complaint: Vomiting and lethargy Patient age: 8 years old Weight: 30 kg

Recommended Supplies

• Manikin : Any model to reflect age of patient (8 years old)
• Moulage: None
• Resources: PALS card and/or length-based tape (e.g., Broselow), local DKA pathways/procedures, if applicable
• Manikin set up : IV line available x 1 in place with drainage bag
• Point of care tester (for glucose/VBG/K+)
• Intraosseous equipment including E-Z IO, needle, stabilizer, and connectors; saline flushes
• ECG machine
• Cardiac monitor
• Continuous oximeter
• Simple facemask
• Non-rebreather
• Nasal cannula
• Oxygen tubing
• Medications: Normal saline, IV insulin, sodium bicarbonate, mannitol, hypertonic saline, ondansetron (ODT or IV), D10 1⁄2 NS (optional)

Supporting Files

• Point-of-care labs (VBG/CBG, glucose, electrolytes)
• First ECG showing sinus tachycardia with signs of hypokalemia
• Second ECG (if insulin started without checking/giving potassium) showing Torsades de Pointes

Participants/Roles

• Team Leader
• Airway Manager
• Survey Physician
• Medication Preparer
• Medication Giver
• +/- Family Liaison
• Consultant (PICU or Endocrine)
• Embedded participants can play a nurse, respiratory therapist, or tech.
• Standardized patient (actor or faculty) to play patient’s parent

Team roles may need to be adjusted in order to suit local practices and norms

Prerequisite Knowledge

• PALS protocols
• General knowledge of emergency medicine
• Simulation implementation and debriefing experience
• Any stage of training (PGY-1,2 for basic case, PGY3+ advanced case)
• Completed PALS certification

Case Alternatives

• If residents fail to recognize DKA within 5 minutes of the case (e.g., gives normal saline boluses, +/- administers antibiotics, +/- gives pressors), the patient will become more lethargic (cerebral edema) and will need emergent airway management.
• If intubation is performed, the patient will become more acidotic and hypotensive.
• For advanced learners, the initial ECG will show u-waves and a wide QRS. If this is not recognized, the patient will develop torsades (and ultimately ventricular tachycardia if not recognized). (See Stage 2 )

Virtual Resus Room

This simulation case can be run virtually using Google Slides and Zoom from the Virtual Resus Room (Peds DKA) page.

PC1.  Emergency Stabilization PC2.  Performance of Focused History & Physical Exam PC3.  Diagnostic Studies PC4. Differential Diagnoses and Management PC5.  Pharmacotherapy PC9. General Approach to Procedures PC14 . Vascular Access PC15. Medical Knowledge ICS1.  Patient Centered Communication ICS2.  Team Management

• Kuppermann N, Ghetti S, Schunk JE, et al. Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis. N Engl J Med. 2018;378:2275-2287. PMID 29897851
• Wolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. 2006;29:1150-1159. PMID 16644656
• Wolfsdorf J, Craig ME, Daneman D, et al. Diabetic ketoacidosis. Pediatr Diabetes. 2007;8(1):28-43. PMID 17341289
• Glaser NS, Stoner MJ, Garro A, et al.; Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group. Serum Sodium Concentration and Mental Status in Children With Diabetic Ketoacidosis. Pediatrics. 2021 Sep;148(3):e2021050243. doi: 10.1542/peds.2021-050243. Epub 2021 Aug 9. PMID: 34373322 .
• Kuppermann N. Pediatric DKA: Don’t Fear the Fluids! EMRA Cast, 2020.
• Glaser N, Kuppermann N. A Sweet New Year to All – DKA . PEM Podcast, 2020.
• Woods J, Bukowski J. PEM Pearls: Treatment of Pediatric Diabetic Ketoacidosis and the Two-Bag Method . Acad Life in Emerg Med, 2017. .

Hyperglycemia

Evaluation to identification of DKA

• Team leader assigns tasks
• Obtains brief history from parent
• Performs primary survey
• Request patient placement on continuous cardiac monitor
• Performs focused physical exam
• Verbalizes recognition of shock
• Obtains point-of-care glucose (high)
• Obtains vascular access
• IO or ultrasound-guided peripheral IV preferred, if peripheral access is unsuccessful
• Verbalizes recognition of hyperglycemia
• Obtains point-of-care VBG/CBG and electrolytes (abnormal)- if extended electrolytes are ordered (Mg+, PO4-, they are not available during case)
• Verbalizes hypokalemia on POC testing OR obtains ECG showing hypokalemia-related changes
• Discusses progress/plan of care with the family

* Unbolded items may be excluded depending on local practices and norms

Physical Exam

Instructor Notes: Changes and Case Branch Points

DKA Stabilization

Identification of DKA through start of insulin drip and IV fluids

• Verbalize recognition of DKA, complicated by hypokalemia
• Administer 10 mL/kg normal saline for moderate dehydration
• Reassess perfusion status following initial bolus
• Reassess mental status following initial bolus
• Reassess glucose level following initial bolus
• Begins IV insulin AFTER saline bolus is completed (0.05-0.1 units/kg/hour)
• Begins IV potassium for K<3.5 mEq/L (0.5 mEq/kg over 1 hour) – can be given peripherally as bolus

Case Conclusion and Disposition

Time 1 hour after arrival through reassessment (physical exam and labs)

• Verbalize need for repeat neuro checks for cerebral edema evaluation
• Verbalize need for q 2 hour electrolyte/glucose monitoring
• Orders VBG + electrolytes STAT if worse in any way
• Explains diagnosis to parent and how it relates to the patient presentation
• Consults PICU and/or Endocrine for admission (if not done in Stage 2)

TIME ADVANCE:

Instructors: please state “time has advanced 1 hour since the patient arrived at the ED.”

Shock is the state where blood flow to tissues/organs flow does not adequately meet the demand. Children are more susceptible to cardiovascular compromise from shock because of both physiologic differences (compared with adults) and their limited reserve.

• In general, hypotension is a late finding in pediatric shock. Assessment of perfusion status (e.g., capillary refill) may give an early indication: delayed capillary refill suggests “cold shock” (cardiovascular or hypovolemic source) and very brisk capillary refill suggests “warm shock” (e.g., anaphylactic or distributive etiology)
• Another early sign of shock in children is tachycardia and decreased capillary refill, compared to a low blood pressure.

In general, the evaluation of a critically ill child requires quick assessment of the pediatric triangle (appearance, breathing, color) in conjunction with the primary survey with an emphasis on the clinical status

• Appearance: Mental status, level of arousal, and changes in speech/cry
• Work of breathing: Note presence of abnormal breath sounds, retractions, nasal flaring, grunting, apnea
• Circulation to skin: Note presence of pallor, delayed capillary refill, mottling, cyanosis

Primary survey:

• Airway: Does the patient have a patent airway?
• Breathing: Auscultate for bilateral breath sounds
• Circulation: Assess for presence/absence of pulses and degree of peripheral perfusion, cardiac sounds, liver distension
• Disability: Report Glasgow Coma Scale, examine pupils, D * for dextrose
• Exposure: Allow for adequate visualization of the patient

Interpret signs/symptoms and laboratory changes of DKA including hyperglycemia and acidosis (evaluation)

• Hyperglycemia >200 mg/dL
• Acidosis: Venous pH <7.3 or HCO 3 – <15 mEq/L
• Mild DKA (pH: 7.2-7.3) (HCO 3 -: 10-14 mEq/L)
• Moderate DKA (pH: 7.1-7.2) (HCO 3 : 5-9 mEq/L)
• Severe DKA (pH: <7.1) (HCO 3 -: <5 mEq/L)
• The initial step in DKA treatment is assessment of dehydration status, weight, and mental status.
• Blood glucose level
• Blood beta-hydroxybutyrate (may not be available POC in all locations)
• Urine ketones (may be found on urine dipstick)
• Blood glucose level (for more accurate values)
• Serum electrolytes (including bicarbonate – allows for anion gap calculation)
• BUN/creatinine
• Complete blood count
• Calcium, phosphorous, magnesium
• Saline (see detailed discussion below)
• +/- Potassium
• Avoidance of bicarbonate (lack of benefit and potential for harm)

Cerebral injury (or cerebral edema) is rare. Its clinically significant incidence is between 0.3-0.9% of episodes in children with DKA. (Many or most others with DKA will have subclinical cerebral edema without neurological signs). It is more common in children with DKA than adults, and those with the most severe DKA are at highest risk for the cerebral complications. It may be present prior to DKA treatment or during it (between 3-12 hours after treatment begins). The cause is not completely understood. Early work thought it may be the rate of fluid administration but this is being challenged with current lines of research.

– “Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis”: June 14, 2018 — N Engl J Med 2018; 378:2275-2287 (DOI: 10.1056/NEJMoa1716816 )

• Severely acidotic on original presentation
• High BUN on presentation (suggests greater hypovolemia)
• Insufficient rise of sodium level when DKA treatment starts
• Younger age (<3-5 yrs old) on presentation (because diagnosis is often delayed)
• Abnormal verbal or motor response to pain
• Posturing (decorticate or decerebrate)
• Double vision or cranial nerve palsy (III, IV, VI)
• Abnormal respiratory pattern (Cheyne-Stokes, apnea, grunting, tachypnea)
• Age-inappropriate incontinence
• Abnormal, fluctuating or declining mental status after therapy begins (including agitation)
• Abnormal heart rate sowing (declining by more than 20 beats) that is not explained by sleep or improved intravascular volume status
• Lethargy or irritability*
• Elevated blood pressure (e.g., diastolic BP >90 mmHg)
• *Especially if begins/resumes after DKA treatment initiated
• 1 major plus 1 minor criteria (if age <5 years old)
• Avoid drugs that increase ICP
• Elevate head of the bed 30 degrees
• Hyperosmolar therapy:
• First line treatment: Mannitol 0.5-1g/kg IV over 10-15 minutes. May repeat in 30 minutes.
• Second line treatment: Hypertonic saline 2.5-5 mL/ kg over 30 minutes
• Neurosurgery consult for possible ICP measuring
• IV saline to improve intravascular compromise
• 10-20 mL/kg normal saline or lactated ringers
• Ensure adequate airway and assist ventilation as needed
• Supplemental oxygen as needed to maintain a normal O 2 level
• Avoid intubation if possible
• If intubation is necessary, hyperventilate to maintain the pCO 2 they had before they decompensated. Reduce this over several hours.

Manage hypokalemia and hyperglycemia with potential of hypoglycemia in the setting of insulin administration (application)

Patients in severe DKA may also need supplemental IV potassium. Since the goal of insulin administration is closure of the anion gap, supplemental dextrose may be needed when the serum glucose level falls below 250.

When adding dextrose for glucose <250 mg/dL, you may use the “2- bag method”.

• 4 mL/kg/hr for the first 10 kg body weight
• 2 mL/kg/hr for the second 10 kg body weight
• 1 mL/kg/hr for the remaining weight
• In this case (pt weighs 30 kg): 70 mL/hr
• In this case: 105 mL/hour
• Finally, determine which percentage of which bag to give.

Two-Bag Method of IV Fluids in Hypoglycemia

• 1 bag normal saline
• 1 bag D10NS
• 1 bag D12.5 NS
• PRN dextrose

Hypokalemia in the setting of DKA

Hypokalemia on presentation signifies a profound total potassium deficit. Caution with IV insulin and bicarbonate therapy is warranted, because it could further drop the potassium levels. Davis et al. 2016 presented a case of profound hypokalemia associated with DKA (Pediatr Diabetes Feb; 17 (1): 61-65). In this case, the patient’s potassium level was 1.3 mEq/L. 0.3 mEq/kg KCI over 1 hour was initiated and insulin held until potassium level was 2.7 mEq/L.They reported that their institution had a policy which prevented them from giving a more aggressive replenishment of 0.5 mEq/kg over an hour potassium via a peripheral line. They opted to avoid risks associated with central line placements. Additionally, 30 mEq/L potassium acetate and 30 mEq/L potassium phosphate were given at 1.5x maintenance.

PFCCS (Pediatric Fundamental Critical Care Support) recommends a conservative IV potassium replacements regimen:

• If K+ 3.0-3.5 mEq/L, administer 0.25 mEq/kg KCL over 1 hour.
• If K+ 2.5-3.0 mEq/L, administer 0.5 mEq/kg over 2 hours.
• If K+ <2.5 mEq/L, administer 0.75 mEq/kg over 3 hours, with checking of the K level half-way through this infusion.

Evaluation of a critically ill child should include obtaining a history from all possible sources including EMS, old records (if time), and especially caregivers. Paying attention to details such as trauma or recent illness may give hints toward identifying the underlying pathophysiology. A history of polyuria, polydipsia, increased hunger and weight loss may suggest undiagnosed diabetes. Children may present with DKA after a mild illness so a review of systems should also include evaluation for infection symptoms.

Compassionate, understandable communication with caregivers is critical, as they are strong partners in the treatment of their children. This should not impede lifesaving treatment, but if at all possible, a member of the treatment staff should be assigned to help communicate with parents. Failure to provide a communication liaison may result in anxious parents that may obstruct care. When not actively resuscitating (as in this case), the physician should be able to communicate with patients throughout the child’s care. For complicated concepts, like DKA, it is important to ensure the caregivers understand the explanations being given to them.

Teams may use different frameworks to improve team dynamics and communication. Below are a few definitions that may be helpful to discuss, adapted from the  AHRQ TeamSTEPPS Pocket Guide .

• Brief : Short session prior to start of encounter to share the plan, discuss team formation, assign roles and responsibilities, establish expectations and climate, anticipate outcomes and likely contingencies
• Huddle : Ad hoc team discussion to re-establish Situation Awareness; designed to reinforce plans already in place and assess the need to adjust the plan
• Callout:  A strategy used to communicate critical information during an emergent event. Helps the team prepare for vital next steps in patient care. (Example: Leader- “Airway status?”; Surveying provider- “Airway clear”; Leader- “Breath sounds?”; Surveying provider- “Breath sounds decreased on right”)
• Check-back: A closed-loop communication strategy that requires a verification of information ensuring that information conveyed by the sender is understood by the receiver as intended. The sender initiates the message; the receiver accepts it and restates the message. In return, the sender verifies that the re-statement of the original message is correct or amends if not. (Example: Leader- “Give diphenhydramine 25 mg IV push”; Med Prep- “Diphenhydramine 25 mg IV push”; Leader- “That’s correct”)
• S = Situation (What is going on with the patient?)
• B = Background (What is the clinical background or context?)
• A = Assessment (What do I think the problem is?)
• R = Recommendation (What would I do to correct it?)
• Situation monitoring: The process of continually scanning and assessing a situation to gain and maintain an understanding of what is going on around you.
• Situation awareness:  The state of “knowing what’s going on around you.”
• Shared mental model: Result of each team member maintaining situation awareness and ensures that all team members are “on the same page.” An organizing knowledge structure of relevant facts and relationships about a task or situation that are commonly held by team members.
• STEP:  A tool for monitoring situations during complex situations. A systematic method to review  S tatus of patient,  T eam members’ performance and status,  E nvironment, and  P rogress towards goal.
• Cross-monitoring: A harm error reduction strategy that involves 1. Monitoring actions of other team members 2. Providing a safety net within the team. 3. Ensuring that mistakes or oversights are caught quickly and easily. 4. “Watching each other’s back.”
• CUS:  Signal phrases that denote “I am  C oncerned,” “I am  U ncomfortable,” and “This is a  S afety Issue.” When spoken, all team members should understand clearly not only the issue but also the magnitude of the issue.

Download Case 5 supporting files

• ECG 1 interpretation: ECG with signs of hypokalemia. Image from Dr. Ilana Bank.
• ECG 2 interpretation: ECG with torsades de pointes. Image from Dr. Ilana Bank.

For the embedded participants playing the role of the patient and mother

Case Background Information

You are bringing your daughter to the ED for vomiting and “tiredness.”

Over the past week the whole family has had the “flu,” with intermittent fevers, myalgias and fevers. Her 3 siblings, however, are all feeling better – but she doesn’t seem to be back to herself. Additionally, for the last 2 days she has been complaining of stomach aches with “too many to count” episodes of vomiting (NB/NB). You took her to an urgent care earlier in the day and they told you that some children take longer to recover from illnesses than others. You’re not satisfied with that response.

Who are the Learners?

Emergency medicine residents

This case is specifically aimed at first and second year residents who should have experience in gathering information from patients and families, and standard medical treatments and procedures. They may be less familiar with escalating medical therapies when first measures are not successful.

Standardized Patient Information

Mother: Your demeanor is overall anxious and concerned. You are a nervous parent with limited medical acumen. Interrupt the doctors often with questions – but do not be belligerent or aggressive. You are especially concerned about her stomach-ache and really want to know if she will need surgery. If given space, tell the team about your friend’s daughter who has a stomach-ache and then needed surgery, and then ask repeatedly “is this the same thing?” Her nausea is making you very anxious and want it managed quickly. Something is VERY wrong with your child and you know it. You keep giving her Motrin and Robitussin, but it is not making her any better.

Patient: She doesn’t contribute much. She is awake, tired appearing, not moving a lot on the bed, but intermittently rubs her stomach, clutches her vomit bag (if offered one) and talks about feeling like she might throw up. When examined, she cannot specifically tell them where your pain is – “it’s everywhere.” She is alert and oriented if asked. She is also thirsty if asked.

Patient Information

(Please remember not to offer any of this information, but when asked please respond while remaining in character.)

• CHIEF COMPLAINT: “My stomach hurts.”
• AGE: 8 years old
• ADDITIONAL HISTORY : “I had a cold last week, my whole body hurt and since then I feel crummy.”
• PAST MEDICAL HISTORY : None
• SOCIAL HISTORY: None, no recent travel. They have never left California.
• FAMILY HISTORY : Grandma has trouble with sugars – offer only if specifically asked
• PAST SURGICAL   HISTORY : None
• MEDICATIONS:  None
• ALLERGIES: No known drug allergies
• IMMUNIZATIONS: Up-to-date
• BIRTH HISTORY : Unremarkable. She was born full term, no medical complications (patient is 8 years old, ok if they don’t ask about birth history)

Potential Dialogue

IMPORTANT: Do not offer unsolicited information. Please allow the learners to ask questions. Do not offer information unless they ask you.

Things Mom could say without being asked:

• “All the vomiting has made her lose weight. She keeps eating but is so skinny. I think it’s the vomiting.”
• “Everyone else got better, why isn’t she getting better?”
• “She is such a healthy child, she is never sick and never complains. I know something is wrong.”

Things you might say triggered by events in the scenario:

The learners enter the room to find a patient who is dry, uncomfortable, and tired appearing – she is mildly somnolent but fully arousable. They immediately place the patient on a bedside monitor and recognize that the patient is in early hypovolemic shock. Access needs to be obtained and might be difficult; the residents can place an IO and an IV fluid bolus should be ordered. Initial blood work should also be ordered at this time – including point of care glucose – the result of which should immediately prompt the residents to move down the DKA management pathway.

After completing a physical examination and obtaining an appropriate history, the learners should note that the patient appears to be worsening – her blood pressure has decreased slightly and remains tachycardic. At this point they discuss the risk of cerebral edema with aggressive fluid management. Patient’s perfusion status remains stable and BP is still above 5% for her age range so conservative management should continue. Insulin is ordered and potassium is measured. Potassium returns 3.1 mEq/L, which should prompt the learners to recognize the need to give potassium (either as a bolus or incorporated into maintenance fluid) prior to the initiation of the insulin drip (regardless of whether they additional IVF). Patient remains stable and starts to hemodynamically improve as the second bolus starts.

No signs of cerebral edema are noted on 1 hr neurologic check. She is admitted to ICU, and the endocrine team is consulted, who will follow the patient in the unit. Prior to the end of the case, DKA diagnosis is explained to the patient and her mother, and DKA education is started.

Anticipated Management Mistakes

• Inadequate IV access: Learners may be hesitant to perform IO/ ultrasound-guided peripheral IV (USGPIV) access. Some may be unfamiliar with it or may be concerned that it is painful or frightening for parents to watch. However, with need for IVF, IV insulin, and potassium, access is critical. Furthermore, in critically ill patients, anticipating a need for access is crucial. While IO access and USGPIV are becoming more mainstream, it may be helpful to have a nurse prompt with “we do this all the time”. If learners fail to recognize how ill the child is, a nurse may prompt with “she seems pretty sick, I worry she may get worse quickly.”
• Intubation of a patient in DKA: It would be unlikely in a patient with a fairly normal mental status for intubation to be considered. However, some learners may bring an element of simulation artifact (“it is sim so this is going to go downhill fast”) to the case. In this scenario, intubation leads to worsening acidosis, and PEA requiring CPR and epinephrine. If the conversation heads toward intubation, it may be helpful to discuss the risk/benefit of intubation in an acidotic patient who is relying on respiratory compensation. It is actually quite dangerous to intubate a patient such as this unless the patient is severely obtunded and not maintaining respiratory effort or protecting their airway. It is very hard to be able to compensate as well as the patient can with a ventilator.
• Excessive fluid resuscitation: Some of our learners may provide aggressive fluid resuscitation in an attempt to normalize heart rate and blood pressure. Concerns for cerebral edema increase with aggressive fluid management. This however, is controversial. Please refer to the Kuppermann et al. trial as a point of discussion.

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Diabetic ketoacidosis

• Overview  
• Theory  
• Diagnosis  
• Management  
• Follow up  
• Resources  

When viewing this topic in a different language, you may notice some differences in the way the content is structured, but it still reflects the latest evidence-based guidance.

Diabetic ketoacidosis (DKA) is characterised by a biochemical triad of hyperglycaemia (or a history of diabetes), ketonaemia, and metabolic acidosis, with rapid symptom onset.

Common symptoms and signs include increased thirst, polyuria, weight loss, excessive tiredness, nausea, vomiting, dehydration, abdominal pain, hyperventilation, and reduced consciousness.

Successful treatment includes correction of volume depletion, ketogenesis, hyperglycaemia, electrolyte imbalances, and comorbid precipitating events, with frequent monitoring.

Complications of treatment include hypoglycaemia, hypokalaemia, pulmonary oedema, and acute respiratory distress syndrome.

Cerebral oedema, a rare but potentially rapidly fatal complication, occurs mainly in children. It may be prevented by avoiding overly rapid fluid and electrolyte replacement.

DKA is an acute metabolic complication of diabetes that is potentially fatal and requires prompt medical attention for successful treatment. It is characterised by absolute or relative insulin deficiency and is the most common acute hyperglycaemic complication of type 1 diabetes mellitus. [1] Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2009 Jul;32(7):1335-43. http://care.diabetesjournals.org/content/32/7/1335.full http://www.ncbi.nlm.nih.gov/pubmed/19564476?tool=bestpractice.com [2] Joint British Diabetes Societies for Inpatient Care. The management of diabetic ketoacidosis in adults. Mar 2023 [internet publication]. https://abcd.care/sites/abcd.care/files/site_uploads/JBDS_Guidelines_Current/JBDS_02_DKA_Guideline_with_QR_code_March_2023.pdf

This topic covers diabetic ketoacidosis in adults. Bear in mind that people aged 16 to 18 years may be managed by either a paediatric team or an adult medical team according to local arrangements. The Joint British Diabetes Societies for Inpatient Care guideline recommends following paediatric guidelines if the patient is being managed by a paediatric team, and following adult guidance if they are being managed by an adult team. [2] Joint British Diabetes Societies for Inpatient Care. The management of diabetic ketoacidosis in adults. Mar 2023 [internet publication]. https://abcd.care/sites/abcd.care/files/site_uploads/JBDS_Guidelines_Current/JBDS_02_DKA_Guideline_with_QR_code_March_2023.pdf [3] British Society for Paediatric Endocrinology and Diabetes. BSPED interim guideline for the management of children and young people under the age of 18 years with diabetic ketoacidosis. April 2020 [internet publication]. https://www.bsped.org.uk/media/1798/bsped-dka-guideline-2020.pdf

In the UK, the British Society for Paediatric Endocrinology and Diabetes publishes guidance for the management of DKA in children. [3] British Society for Paediatric Endocrinology and Diabetes. BSPED interim guideline for the management of children and young people under the age of 18 years with diabetic ketoacidosis. April 2020 [internet publication]. https://www.bsped.org.uk/media/1798/bsped-dka-guideline-2020.pdf

History and exam

Key diagnostic factors.

• known diabetes or features of diabetes
• nausea and/or vomiting
• abdominal pain
• dehydration
• hyperventilation
• reduced consciousness
• presence of risk factors
• hypothermia

Other diagnostic factors

• acetone smell on breath

Risk factors

• inadequate or inappropriate insulin therapy
• myocardial infarction
• pancreatitis
• hyperthyroidism
• drugs (e.g., corticosteroids, thiazides, pentamidine, sympathomimetics, second-generation antipsychotics, cocaine, immune checkpoint inhibitors, or SGLT2 inhibitors)
• Cushing's syndrome
• Hispanic or black ancestry
• bariatric surgery

Diagnostic investigations

1st investigations to order.

• venous blood gas
• blood ketones
• blood glucose
• urea and electrolytes
• full blood count

Investigations to consider

• pregnancy test
• amylase and lipase
• cardiac enzymes
• creatinine kinase
• chest x-ray
• liver function tests
• blood, urine, and sputum cultures

Treatment algorithm

Initial systolic blood pressure <90 mmhg, initial systolic blood pressure ≥90 mmhg, contributors, expert advisers, edward jude, md, mrcp.

Consultant Diabetologist and Endocrinologist

Tameside and Glossop Integrated Care NHS Foundation Trust

Honorary Professor, University of Manchester

Honorary Professor, Manchester Metropolitan University Manchester

Disclosures

EJ declares that he has no competing interests.

Acknowledgements

BMJ Best Practice would like to gratefully acknowledge the previous team of expert contributors, whose work has been retained in parts of the content:

Aidar R. Gosmanov, MD, PhD, FACE

Associate Professor of Medicine

Division of Endocrinology

Albany Medical College

Chief, Endocrinology Section

Albany VAMC

Laleh Razavi Nematollahi, MD

Assistant Professor of Medicine

Case Western Reserve University

ARG and LRN declare that they have no competing interests.

Peer reviewers

Gerry rayman, md, frcp.

Consultant Physician and Head of Service

Diabetes and Endocrine Centre and the Diabetes Research Unit

Ipswich Hospitals NHS Trust

GR has been paid for advisory board meetings with the following companies: Sanofi Aventis, Abbott Diabetes UK, Lilly Diabetes, and Bayer. GR has received lecture fees from Sanofi Aventis, Abbott Diabetes UK, Lilly Diabetes, Novo Nordisk, and Napp Pharmaceuticals Ltd.

Ketan Dhatariya, MBBS, MSc, MD, MS, FRCP, PhD

Honorary Professor of Medicine

Norwich Medical School, University of East Anglia

Consultant Diabetes & Endocrinology

Norfolk and Norwich University Hospitals NHS Foundation Trust

KD is the chair of the Joint British Diabetes Societies for Inpatient Care. KD has received honoraria from Diabetes Professional Care to speak at its annual meeting about these guidelines. No other reimbursement has been received from commercial organisations with respect to these guidelines. KD has helped to develop educational materials on this subject for the European Association for the Study of Diabetes, but did not receive any reimbursement. For other work as the chair of JBDS, KD has received honoraria from Lilly for developing educational material.

Annabel Sidwell

Section Editor, BMJ Best Practice

AS declares that she has no competing interests.

Luisa Dillner

Head of Research and Development, BMJ

LD declares that she has no competing interests.

Head of Editorial, BMJ Best Practice

AE declares that she has no competing interests.

Rachel Wheeler

Lead Section Editor, BMJ Best Practice

RW declares that she has no competing interests.

Julie Costello

Comorbidities Editor, BMJ Best Practice

JC declares that she has no competing interests.

Adam Mitchell

Drug Editor, BMJ Best Practice

AM declares that he has no competing interests.

Differentials

• Hyperosmolar hyperglycaemic state (HHS)
• Lactic acidosis
• Starvation ketosis
• The management of diabetic ketoacidosis in adults
• Type 1 diabetes in adults: diagnosis and management

Calculators

Glasgow Coma Scale

Venepuncture and phlebotomy animated demonstration

How to perform an ECG animated demonstration

Patient information

Diabetes type 2: should I take insulin?

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• v.79; 2022 Jul

Successful medical management of diabetic ketoacidosis at first presentation in a child with type 1 diabetes: A case report

Shriya sharma.

a Nepalese Army Institute of Health Sciences, Kathmandu, Nepal

Aakriti Adhikari

Samikshya adhikari, sabin poudel, gaurab mainali, sumit kumar yadav.

b Shree Birendra Hospital, Kathmandu, Nepal

Associated Data

Introduction and importance.

Diabetic ketoacidosis (DKA) is considered to be a common presentation of type 1 diabetes mellitus in children. It occurs when absolute or relative insulin insufficiency prevents glucose from entering the cells for use as metabolic fuel, causing the liver to quickly break down fat into ketones for use as fuel source. As a result, ketones are overproduced, accumulating in the blood and urine making the blood acidic.

Case presentation

A 4 years and 8 months old child presented with the complaint of abdominal pain and vomiting along with polyurea, polydipsia and polyphagia. Routine examination of blood revealed that increased random blood glucose level. Once diagnosed, DKA was managed with fluid and insulin therapy with close monitoring and supervision.

Clinical discussion

DKA can be easily diagnosed. Proper management should be done on time to prevent complications like hypokalemia, hyponatremia leading to cerebral edema and shock.

Conclusions

Diabetic awareness programs and school educational tutorials are beneficial for community awareness of the signs and symptoms of diabetes.

• • Diabetic ketoacidosis (DKA) is considered to be a common presentation of type 1 diabetes mellitus in children.
• • Severe fall in insulin levels leads to increase in lipolysis which will lead to increase in level of ketone bodies resulting metabolic acidosis and compensatory respiratory alkalosis.
• • DKA is diagnoses on the basis of hyperglycemia, metabolic acidosis and ketonuria and severity is categorized on the basis of acid-base status.
• • Early medical management and close monitoring could prevent complications like cerebral edema, mental confusion, shock and death.

1. Introduction

Type 1 diabetes is due to autoimmune destruction of pancreatic beta cells which leads to insufficient insulin production resulting in hyperglycemia [ 1 ].The common symptoms presenting in type 1 diabetes are polyurea, polydipsia, and weight loss [ 2 ]. Severe fall in insulin levels leads to increase in lipolysis which will lead to increase in level of ketone bodies resulting metabolic acidosis and compensatory respiratory alkalosis [ 3 ]. Diabetes ketoacidosis (DKA) is the common presentation of type 1 diabetes mellitus in children. The prevalence of onset of diabetic ketoacidosis among type 1 diabetes mellitus was found to be 26.3% in one of the studies [ 4 ]. Common complications observed due to ketoacidosis are electrolyte abnormalities like hypokalemia, hyponatremia leading to cerebral edema and shock [ 5 ].

If Diabetic ketoacidosis is not treated on time, the compensatory mechanism will fail soon and lead to cerebral edema, mental confusion, unconsciousness, coma and death [ 3 , 6 ]. DKA is the most common cause of death in children and adolescents with type 1 diabetes and cause of half of all deaths in diabetic patients under the age of 24 years [ 7 ]. Immediate and aggressive intervention is required. Early medical management could prevent complications like cerebral edema, mental confusion, shock and death. Here, we present a successful medical management of a diabetic ketoacidosis as a first presentation in a child with type 1 Diabetes mellitus. This case has been reported accordingly in line with SCARE 2020 criteria [ 8 ].

2. Case presentation

A 4 years 8 months old school going male child presented to the Emergency department of Shree Birendra Hospital with complaints of abdominal pain in periumbilical region for 1 day. Pain was mild, acute on onset, non-radiating associated with irritability. He also had a history of multiple episodes of vomiting for the last 3 days. Vomitus was non-projectile consisting of partially digested food particles and water. It was non-bile stained, was not mixed with blood, and was non-foul smelling. He also had a history of polyuria, polydipsia, and polyphagia for 7 days. Day by day there was an increase in frequency of urine which was associated with increased water intake. There is a history of a 2 kgs weight loss within a week. He was born healthy at term following an uncomplicated pregnancy and was the second child of a non-consanguineous marriage. There was no any family history of type I DM and any chronic illness.

On physical examination, the child was irritable and dehydrated with a dry tongue and mucosa. Vitals recorded at the time of admission were as follows; blood pressure of 80/50 mmHg, pulse rate of 128 beats/min and were low volume, respiratory rate of 24 breaths/minute, oxygen saturation of 95% on room air, and body temperature were 98 °F. Systemic examinations were normal.

Routine examination of blood revealed an increase in random blood glucose level with value of 448 mg/dl (ref. 140 mg/dl) and hyponatremia with value of 130 mEq/L (ref. 136–145 mEq/L), however serum potassium, urea and creatinine levels were normal. Urine examination revealed that the urine was acidic, acetone positive and sugar was present in urine. Arterial blood gas analysis showed pH 7.23 (ref. 7.35–7.45), pCO 2 31 (ref. 35–45 mmHg), HCO 3 − 13.21 (ref. 22–26mmoL/l), and PO 2 102 (80–105 mmHg). Hematological examination was unremarkable.

Based on hyperglycemia, metabolic acidosis, and ketonuria a diagnosis of DKA was made and management was initiated. The child was shifted to Pediatrics intensive care unit (PICU) where he was given intravenous fluid of 320 ml normal saline IV over 1 hour at the rate of 20 ml/kg. Similarly, regular insulin 0.5 ml hourly at the rate of 0.05 unit/kg hr (1ml insulin in 23ml NS) and injection ceftriaxone 500 mg IV 12 hourly at the rate of 63 mg/kg/day were administered for the next 23 hours. The child was kept in N/2 IV Fluid 100 ml/hourly with 1mEq KCl in each 100 ml IV fluid. If random blood sugar fell below 250 mg/dl, N/2 IV fluid and 5% dextrose at 100ml/hourly with 1mEq KCl in each ml of 100 ml IV fluid was indicated. We kept our patient on nil per oral. Similarly, if random blood sugar falls below 200 mg/dl, N/2 IV fluid and 10% dextrose at 100 ml/hourly was indicated.

Further, the vitals were monitored hourly; random blood sugar and neurological assessment were done 2 hourly; renal function test, electrolyte were monitored 6 hourly. X-ray of chest to rule out pulmonary infections such as pneumonia, ultrasonography of abdomen to rule out any organ damage, ophthalmology consultations to rule out papilloedema were done. There were no significant findings on any one of them. After 5 days on PICU, our patient's symptoms gradually improved. He was started on an oral fluid and liquid diet. The random blood glucose levels monitored at different time intervals were in the normal range. We discharged the patient after 7 days of admission with advice of Insulin Glargine 6 units sc once a day and Insulin Lispro 4 units before breakfast, lunch and dinner. The patient was properly instructed to follow up after 1 week for insulin management as per glucose report.

3. Clinical discussion

DKA is life threatening complications of uncontrolled diabetes mellitus if proper intervention is not done on time [ 9 ]. Risk of developing DKA at manifestation of diabetes is high in young children (<2 years), girls, children of ethnic minority status, low socio-economic status [ [10] , [11] , [12] ]. Successful management of diabetic ketoacidosis depends upon swift diagnosis, regular monitoring of clinical and biochemical parameters with prompt intervention. The diagnosis of DKA can be made on the basis of biochemical criteria of random blood glucose level greater than 200mg/dl with a venous pH of level <7.3 and/or a bicarbonate (HCO3) level of <15 mmol/L; ketonemia and ketonuria [ 11 ]. Early detection of diabetic ketoacidosis in our case led to proper medical management of a patient preventing him from complications like cerebral edema. However, diagnosis of DKA should not be confused with asthma, hypokalemia, metabolic acidosis, respiratory acidosis, pneumonia, salicylate poisoning, acute abdomen, gastroenteritis etc. [ 13 ].

Muktan et al. in their retrospective study found that polyurea, polydipsia, weight loss, abdominal pain, vomiting as the most common symptoms of DKA [ 14 ]. Our patient also presented with similar symptoms from which we made a provisional diagnosis of DKA after physical examination which was later confirmed by biochemical examination. DKA can be managed in any hospital/private unit or in a pediatric inpatient ward in case of children by trained nursing and medical personnel.

Rosenbloom et al. in his study had described the management of Diabetic Ketoacidosis depends on the severity of DKA. The severity of DKA is categorized by acid-base status in which mild DKA has pH 7.2 to <7.3; bicarbonate 10 to <15 mEq/L, moderate DKA has pH 7.1 to <7.2; bicarbonate 5 to 9 mEq/L and severe DKA has pH < 7.1; bicarbonate <5 mEq/L [ 15 ]. Our patient had pH level of 7.23 and bicarbonate level at 13.21. Thus, he had a mild DKA and was treated accordingly.

The child presented with DKA should be closely monitored in the unit. Blood glucose, electrolyte level, neurological assessment, vitals, and urine routine examination should be monitored on hourly basis [ 16 ]. We monitored our patient's vitals hourly; random blood glucose level and neurological assessment 2 hourly; electrolyte, input/output charting, and urine routine examination 6 hourly.

The patient with DKA is treated with intravenous fluids and intravenous insulin if the child is nauseated/vomiting, clinically dehydrated or is not alert [ 17 ]. We managed our patient as per his symptoms. We used normal saline for the first 24 hours to treat and manage dehydration and mild sodium depletion. We kept our patient on Insulin to control increased random blood glucose level. KCL along with intravenous fluids was given to manage the impending hypokalemia. In order to treat and prevent possible bacterial infections, ceftriaxone was given. Since we kept our patient nil per oral, dextrose in intravenous fluids was introduced the next day.

4. Conclusion

We present a case of diabetic ketoacidosis in a child with type 1 diabetic mellitus. It is a life threatening complications if timely intervention is not done. Timely management with fluid therapy along with insulin should be done. Regular monitoring and neurological observation are equally important to prevent complications like cerebral edema. Educational programs, diabetes awareness campaigns, and school educational tutorials can be beneficial for community awareness of the signs and symptoms of diabetes.

Author agreement statement

We the undersigned declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.

We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.

Ethical approval

This is a case report, therefore, it did not require ethical approval from the ethics committee.

Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the editor-in-chief of this journal on request.

Registration of research studies

Not applicable

The study did not receive any grant from funding agencies in the public, commercial or not-for-profit sectors.

Author contribution

All authors: writing the paper, collection of Data, revising it critically for important intellectual content, reviewing, and editing.

Shriya Sharma, Nepalese Army Institute of Health Sciences, Kathmandu, Nepal E-mail: [email protected]

Provenance and peer review

Not commissioned, externally peer-reviewed.

Declaration of competing interest

The authors report no conflicts of interest.

Acknowledgment

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2022.103981 .

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Diabetic Ketoacidosis (DKA) Case Study (45 min)

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Mr. Logan is a 32-year-old male with a history of DM Type I. He presented to the Emergency Department (ED) after being found by his family with decreased LOC, rapid heavy breathing, and fruity breath. His family reports flu-like symptoms for the last few days.

Before even gathering further information - what do you think is going on? Why?

Diabetic Ketoacidosis – he is a Type I Diabetic with heavy breathing (Kussmaul Respirations) and fruity breath. These are classic signs. It’s important to recognize them and immediately begin anticipating the patient’s needs.

What diagnostic or lab tests would you expect the provider to order?

• Complete metabolic panel to check serum glucose, anion gap, potassium, etc.
• Arterial Blood Gas to assess for acidosis
• Urinalysis to look for ketones

The nurse draws a Complete Metabolic Panel and notifies the Respiratory Therapist to obtain an Arterial Blood Gas. Upon further assessment, the patient is oriented x 2 and drowsy. He is breathing heavily. Lungs are clear to auscultation, S1/S2 present, bowel sounds active, pulses present and palpable x 4 extremities. A POC glucose reads >450 (meter max).

Vital signs are as follows: HR 87 RR 32 BP 123/77 SpO 2 96%

Mr. Logan’s labs result and show the following: Glucose 804 mg/dL K 6.1 mEq/L BUN 39 mg/dL pH 7.12 Cr 1.9  mg/dL pCO 2 30 Anion Gap 29 mEq/L HCO 3 – 17 Urine = Positive for Ketones

Using these lab results, explain what is going on physiologically with Mr. Logan.

• His glucose is extremely high and he is positive for ketones, which says that his body is having to break down fatty acids to make energy
• His anion gap is high, meaning there are other “ions” in the system besides the electrolytes – in this case, the extra acids are creating this ‘gap’
• He is in metabolic acidosis because of the ketoacids – this is what’s causing the Kussmaul respirations – his body is trying to breathe off CO2 to bring his pH up
• His potassium is high because the body will kick potassium out of the cells to compensate for an acidotic state. This way instead of having H+ (acids) in the blood stream, we have K+ – this protects many tissues, but puts our heart at risk
• His BUN/Cr are elevated because of the dehydration caused by osmotic diuresis (caused by hyperglycemia and hyperosmolarity)

What is the #1 priority for Mr. Logan at this time?

• The #1 priority for DKA is to get the blood sugar down and get insulin into the system. Getting insulin into the system allows the gluconeogenesis to STOP (so that the body will STOP making ketoacids and start using the glucose it has).
• The #2 priority is fluid replacement due to severe dehydration from osmotic diuresis

The provider writes an order for an Insulin Lispro infusion IV, titrating to decrease blood glucose per protocol, 1L NS bolus NOW, and a continuous infusion of Normal Saline IV at 250 mL/hr, and to change the fluids to D5 ½ NS at 125 mL/hr once the blood glucose level falls below 250 mg/dL.

What is the first action you should take after receiving these orders?

Remind the provider that the only insulin that can be given IV is Regular Insulin and request that he change the order. Call the Pharmacist if you have to

• **Note – most facilities have a computerized ordering that prevents something like this from happening, but it’s important that you know this!!

The provider adjusts the order to Regular Insulin IV infusion.  Orders are also written for hourly POC glucose checks and a q2h BMP.

Why is it important to check a BMP frequently? What are we monitoring for?

• Frequent BMP’s are important to confirm the blood glucose when the POC meter is just reading MAX.  
• It’s also important to monitor the Anion Gap to see when it “closes” – indicating resolution of the acidosis
• We are also monitoring potassium levels. They will start elevated, but insulin drives potassium into the cells – causing it to decrease rapidly.

After 4 hours and another 1L bolus of NS, Mr. Logan’s blood glucose level has dropped to 174 mg/dL, but his anion gap is still 19. The nurse changes his fluids to D5 ½ NS per the order and continues the insulin infusion. The most recent BMP showed a K of 3.7, down from 6.1, so the provider orders to give 40 mEq of KCl PO.

Why is the insulin continued even after the blood glucose decreases?

• The goal is to stop gluconeogenesis and reverse the acidosis. The glucose may fall rapidly while there are still ketoacids being made.
• By giving D5 ½ NS infusion with the insulin, we can continue to bring down the acidosis process while maintaining safe blood sugars.

After another 4 hours, Mr. Logan’s anion gap is now 12, a repeat ABG shows a pH of 7.36 with normal CO 2 and HCO 3 – levels.  The nurse begins to transition Mr. Logan off of the IV infusion to SubQ insulin per protocol.  He is feeling much better and says he’s embarrassed that he had to be brought to the hospital.  

What education can you provide Mr. Logan to help him understand why this happened and how to prevent it from recurring in the future?

• When you are ill, you should check your blood sugar more often as sometimes the body’s healing processes and stress response can make your sugar go higher than normal
• Notify your provider if you’re ill, they may recommend increasing your long-acting insulin
• Notify your provider or go to the ED at the FIRST indication of DKA – fruity breath, heavy breathing, feeling dry and hot, excessive urination, blurry vision, or a blood glucose over 400 mg/dL or over your meter MAX.  
• If you have an insulin pump, make sure it is working appropriately – if not, notify your provider or turn the pump OFF and switch to SubQ insulin until the pump can be fixed
• **Note – if a patient comes in with an insulin pump, it should always be turned OFF – we will manage their sugars with SubQ insulin and don’t want them to receive a double dose.

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PRESENTATION

Clinical pearls, case study: recurrent diabetic ketoacidosis resulting from spurious hypoglycemia: a deleterious consequence of inadequate detection of partial strip filling by a glucose monitoring system.

David A. Price, MD, FACE, is Executive Director of Clinical Affairs at LifeScan, Inc., in Milpitas, Calif.

Note of disclosure:   Dr. Price is an employee of LifeScan, Inc., and holds stock in its parent company, Johnson and Johnson. LifeScan, Inc., manufactures and sells blood glucose monitoring systems for people with diabetes.

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David A. Price; Case Study: Recurrent Diabetic Ketoacidosis Resulting From Spurious Hypoglycemia: A Deleterious Consequence of Inadequate Detection of Partial Strip Filling by a Glucose Monitoring System. Clin Diabetes 1 January 2009; 27 (4): 164–166. https://doi.org/10.2337/diaclin.27.4.164

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E.K., a 28-year-old woman with poorly controlled type 1 diabetes of 10 years' duration, presented with mild nausea, occasional vomiting, dizziness, and recurrent, asymptomatic severe hypoglycemia. In phone consultations with the physician's office in the preceding week, she had reduced her insulin in half because of recurrent, very low (usually asymptomatic) glucose readings but sporadic low glucose levels continued to be problematic. She also had episodic, marked hyperglycemia complicating her dosing decisions. Her patterns of high and low glucose appeared discordant with food intake and insulin dosing.

Her history was remarkable for diabetes and recurrent, intermittent nausea, vomiting, and diarrhea presumed to be manifestations of autonomic neuropathy. She had known hypoglycemia unawareness but had not had problems with unconscious hypoglycemia or seizures. She had no other known autoimmune disorders and no retinopathy or renal dysfunction.

She often missed office appointments and, until recently, had been erratic in her glucose monitoring. At the time of her presentation, she was on 10 units of NPH insulin in the morning and 5 units at night, with small doses of lispro only taken to compensate for very high glucose readings.

Her exam was remarkable for dry mucous membranes and orthostatic hypotension, with a sitting blood pressure of 98/74 mmHg and pulse of 102 bpm and a standing blood pressure of 72/40 mmHg and pulse of 120 bpm. Otherwise, she had normal skin pigmentation and no lipohypertrophy or lipoatrophy, and her neck, heart, lung, abdomen, and extremities were all unremarkable.

Because of the frequent low glucose levels, her insulin was further decreased, down to 7 units in the morning and 2 units at night, and she was provided new bottles of her insulins and test strips. She was instructed to aggressively hydrate and closely monitor her blood glucose and urine ketone levels. Fasting laboratory tests were obtained the next morning. Her A1C was 14%, thyroid-stimulating hormone was 1.84 with a free T4 of 1.5 ng/dl, fasting plasma glucose was 391 mg/dl, cortisol was 31.1 μg/dl (normal 8-24), adrenocorticotropic hormone was 53 pg/ml (normal 9-52), and kidney function, liver function, and anion gap were normal.

She developed increased ketonuria and had continued labile glucose levels and was admitted several days later with mild diabetic ketoacidosis (DKA). She was hydrated, and after parenteral insulin, her insulin dose was increased. Her meter glucose was compared to the lab on several occasions and correlated well.

She was considered stable enough to be discharged for close outpatient follow-up. However, her glucose levels remained chaotic, bouncing from > 400 mg/dl to a “Lo” reading on her meter. Few of the low glucose levels were symptomatic. In response to the profound hypoglycemia, insulin was repeatedly decreased.

Once again, she developed marked hyperglycemia and ketosis and had several emergency room visits for hydration. During each of these visits, her insulin was increased, but because of frequent low glucose readings, she would subsequently decrease her insulin dose. She continued to do poorly and lost weight from her baseline of 150 down to 135 lb.

With her inability to control her glucose levels and impending ketoacidosis, she was readmitted. During this hospitalization, she was instructed to self-monitor her blood glucose with her usual meter (Glucometer Elite, Bayer Diabetes Care, Tarrytown, N.Y.). Several times, her meter displayed “Lo” results that were inconsistent with the hospital meter system and the laboratory. In reviewing the labeling for E.K.'s meter, a diabetes nurse specialist noted that a “Lo” display could occur with incomplete strip filling (also called short or partial filling or short sampling). When her glucose monitoring technique was closely observed, it was discovered that she was visually filling the test strip using a minimal amount of blood. She was not waiting for the beep to confirm adequate strip filling as described in the meter's package instructions.

She was instructed on the proper use of her meter and was discharged. During the next several weeks, E.K. dramatically improved, gaining weight and stabilizing her insulin doses without further occurrences of unexplained hypoglycemia or ketoacidosis. She was then lost to follow-up.

What is the differential diagnosis of falling insulin requirements?

What are the causes of recurrent DKA?

What are the sources of error in self-monitoring of blood glucose (SMBG)?

What are the causes of short sampling?

In this case study, a patient had repeated, asymptomatic low glucose readings resulting in insulin dose reductions and culminating in repeated hospitalizations for DKA. After much detective work in which endocrine (adrenal, pituitary, and thyroid) and metabolic (renal, hepatic) derangements were ruled out, the low glucose readings were found to be the consequence of use error, failure to follow product labeling, and failure of the blood glucose meter to provide an error message with partial strip filling. Instead of an error message, “Lo” or low glucose readings were displayed on the glucose meter. Because both patients and health care professionals use glucose meter data to make treatment decisions, 1 , 2   it is imperative that either results are clinically accurate or an error message is provided if incomplete strip filling occurs.

Although the sample size requirement of many current blood glucose meters is small, short sampling can occur in numerous conditions, including states of vasoconstriction, use of small lancets and shallow lances, desire to minimize blood, and poor or rushed sampling technique. In a recent study by Grady et al., 3   200 subjects were asked to record their daily performance with SMBG using their current meter for 1 month. A simple questionnaire allowed each subject to record daily results from successful tests and to provide information about the reasons for any test failures. The main self-reported failure modes (573 failed tests out of 14,580 individual finger sticks) were “blood drop too small” (32.9%), “error on screen, (32.2%), “can't get blood in strip” (19.3%), and “did not trust the result” (15.5%). These results are evidence that significant problems may be encountered in blood sampling with current meters even by patients who have many years of SMBG experience.

Although current blood glucose meters are designed to detect and provide an error message if an inadequate blood sample is applied to the test strip, several published reports 4 - 7   suggest that inadequate sample application during blood glucose testing with some glucose meters could result in erroneously low glucose readings. The U.S. Food and Drug Administration 8   also recognizes that errors can be attributed to failure of glucose meters to detect an inadequate sample size. However, this is the first published report of deleterious health consequences attributed to this error.

There are several other potential sources of error with SMBG measurements that should be considered with unexplained high and low glucose readings. 2 , 3 , 9   These errors could be related to device factors, physiological factors, patient misuse of the meter, or medication interferences. 10 - 12   Each glucose meter has different enzymes, co-enzymes, mediators, electrode configurations, and manufacturing processes that lead to different characteristics, performance limitations, and interferences. The strip's enzyme activity can be affected by manufacturing variances, exposure to heat and humidity (such as improper storage of the strip outside a vial or failure to close a vial), and strip aging.

Physiological factors that may affect accuracy of some glucose meters include hematocrit extremes, oxygen extremes (for glucose oxidase-based systems) hyperuricemia, hypertriglyceridemia, and hyper-bilirubinemia. In addition, marked dehydration, vasoconstriction, or rapidly changing glucose levels may influence the accuracy of glucose measurement at some body sites.

Patient use errors may result in falsely elevated or decreased glucose measurements. Skin contamination from failure to wash hands is problematic. Misapplication of blood, including underdosing (as in this case), sample smearing, slow application, repeat blood application, or strip movement during application or throughout the test process may affect results. Miscoding meters diminishes the accuracy of the measurements. Incorrect unit of measure settings, date and time settings, or recordkeeping errors can affect glucose reporting and data interpretation.

Finally, medications (acetaminophen, L-dopa, tolazamide, and ascorbic acid) may interfere with some meters. When they occur, these interferences are often associated with levels of medication that significantly exceed physiological or desired levels. In some systems that use the enzyme GDH-PQQ, because it is not specific for glucose, falsely elevated glucose readings may occur in patients treated with agents that contain or are metabolized to maltose (i.e., icodextrin), galactose, or xylose. 13   The associated rise in “glucose” can be quite marked and has been associated with inappropriate insulin doses, severe hypoglycemia, and deaths.

Falling insulin requirements from recurrent hypoglycemia could occur with adrenal dysfunction, progressive renal insufficiency, hypothyroidism, placental insufficiency, changes in food intake or activity, surreptitious insulin administration, insulin errors, or glucose measurement errors. In the described case study, improper test strip filling and its lack of detection was determined to be the casual factor for spurious hypoglycemia, resulting in insulin dose reductions and culminating in repeated ketoacidosis.

Glucose monitoring errors should be considered when glucose results are inconsistent or do not fit the clinical situation. These errors can be related to device or physiological factors, patient misuse, or external interferences and may result in falsely high or low glucose readings.

It is important for patients and clinicians to understand the indications and limitations of the particular glucose meter they are using or recommending and should follow the labeled instructions for the device.

Routine evaluation of patients' SMBG technique is recommended. 14  

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