**7. Complications of diabetic ketoacidosis or it's treatment**

Most of the diabetes-related morbidity and mortality in T1DM can be attributed to compli‐ cations of DKA.

#### **7.1. Hypoglycemia**

**6.8. Monitoring**

268 Type 1 Diabetes

Successful management and early intervention for complications require close monitoring. Timeline in DKA management are listed in Figure-3 [165]. The clinicians should be made a flow chart to obtain all relevant incidents regarding the patient's condition and clinical outcome [192].

**Figure 3.** Timeline in DKA management. GCS:Glascow Coma Scale, CBC:Complete Blood Counting, ECG:Electrocardio‐ gram, HR:Heart Rate, BP:Blood Pressure, BUN:Blood Urea Nitrogen, Cr: Creatinine, WBC:White Blood Cell, CRP:C-reac‐

tive protein, CE:Cerebral edema (adapted from reference 165)

Decrease in the plasma glucose concentration rate should be kept in the range of 50–75 mg/dl/hour. As ketoacidosis is corrected, a rapid decline in plasma glucose levels can be oc‐ cur and this may cause the blood glucose drop to hypoglycemia levels. Hypoglycemia leads to the release of counter-regulatory hormones and this results with rebound ketosis which can lengthen the duration of treatment. In addition to this, severe hypoglycemia can cause cardiac arrhythmias, seizure or loss of consciousness, brain injury including coma or death. The insulin infusion rate should be checked every hour until a steady glucose decline is ach‐ ieved and once the plasma glucose falls to <200-250 mg/dL (11.1-13.88 mmol/L), dextrose should be added to replacement fluids to allow continued insulin administration and avoid hypoglycemia [93].

### **7.2. Rhabdomyolysis and renal failure**

Acute renal failure (ARF) is an uncommon complication of DKA and rarely requires renal replacement therapy and it may be severe and potentially life threatening [196,197]. The eti‐ ology of ARF associated with DKA is multifactorial. The most commonly cited causes are hypovolemia, hypotension and rhabdomyolysis [196]. Prolonged profound ketoacidosis and insulin infusions can lead to severe hypophosphatemia, mainly as a result of intracelluar phosphate shifting [198-201]. Hypophosphatemia can be resulted with rhabdomyolysis. Other risk factors for rhabdomyolysis are severe hyperglycemia and high osmolality. But the pathogenic mechanism leading to rhabdomyolysis in DKA remains unclear. There are few reported cases in literature which had rhabdomyolysis in DKA. There may be no symp‐ toms or the condition can present with a mild increase of creatine kinase or rarely significant acute renal failure necessitating hemodialysis [202-205].

**7.5. Mucormycosis**

zis (Picture from the reference [218])

**7.6. Pulmonary oedema**

**7.7. Pneumomediastinum**

T1DM with DKA infected by mucormycozis [218].

Mucormycosis is an acute, rapidly progressing, and often fatal facultative fungal infection occurs in patients with diabetes who have poor glycemic control and DKA, which have been well established as predisposing factors for fungal growth. Mucormycosis can be classfied; cutaneous, rhino-cerebral, pulmonary, gastrointestinal, central nervous system and dissemi‐ nated [216]. The rhino-cerebral forms develops in patients with diabetes, particularly with the complication such as DKA. The most common symptoms are; facial pain, headache, fe‐ ver, and mental obtundation [217]. In the Figure 4 there is a patient of us, firstly diagnosed

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**Figure 4.** A 15 years old male patient firstly diagnosed T1DM with DKA infected by rhino-orbita-cerebral mucormyco‐

Pulmonary oedema is a rare, iatrogenic complication of DKA. Usually occurs within a few hours of initiation of treatment related with rapid infusion of crystalloids over a short peri‐ od of time. Elderly patients and those with impaired cardiac/renal function are at high risk

Spontaneous pneumomediastinum is a rare pulmonary complication of DKA [220]. Kuss‐ maul breathing and repeated vomiting increases the intra-alveolar pressure; that leads to alveolar rupture; then, the air penetrates peribronchial and perivascular spaces and reach

and monitoring of central venous pressure should be considered [219].

#### **7.3. Peripheral venous thrombosis**

In DKA treatment, patients may require central vascular access for intensive fluid re‐ placement. However, this route of vascular access causes many complications [206] like venous thromboembolism (VTE) [207]. Children with thrombophilia, malignancy, congen‐ ital cardiac disease, acute infection, trauma and surgery have a high risk for complica‐ tions of central venous catheter (CVC) related VTE [206]. In the medical literature there have been few reported cases CVC related VTE in DKA children without known risk factors. [208-210]. Thus, DKA and its treatment may promote a prothrombotic state and activation of vascular endothelium, predisposing to thrombosis. Whilst, DKA has not been identified as an isolated risk factor for CVC-related VTE in adults [211]. Where es‐ sential for, intensive fluid replacement in DKA, these lines should be removed as soon as possible, particularly as CVC-related VTE appears to occur within the first 24-48 hours after insertion [210].

#### **7.4. Pancreatitis**

Acute pancreatitis is a well known complication of DKA in adults [212] but is unusual in childhood. In children with DKA, abdominal pain and vomiting are common. In addi‐ tion to this, patients with DKA also have elevated serum pancreatic enzyme (amylase/ lipase) concentrations without clinical signs or symptoms and without radiographic evi‐ dence of pancreatitis [213,214]. Although hypertriglyceridemia is a known cause of acute pancreatitis and elevated triglyceride concentrations are frequent during DKA, an associ‐ ation between elevated triglyceride concentrations in DKA and pancreatic enzyme eleva‐ tion or pancreatitis have not be showned in the previous studies [213,215]. The mechanism responsible for pancreatic enzyme elevation in DKA has thus remained un‐ clear. Physicians should be aware of this phenomenon so that patients with DKA who have abdominal pain and elevated pancreatic enzymes are not erroneously diagnosed with acute pancreatitis unless in the presence of persistent abdominal pain, which does not resolve with a successful treatment.

### **7.5. Mucormycosis**

**7.2. Rhabdomyolysis and renal failure**

270 Type 1 Diabetes

**7.3. Peripheral venous thrombosis**

hours after insertion [210].

not resolve with a successful treatment.

**7.4. Pancreatitis**

acute renal failure necessitating hemodialysis [202-205].

Acute renal failure (ARF) is an uncommon complication of DKA and rarely requires renal replacement therapy and it may be severe and potentially life threatening [196,197]. The eti‐ ology of ARF associated with DKA is multifactorial. The most commonly cited causes are hypovolemia, hypotension and rhabdomyolysis [196]. Prolonged profound ketoacidosis and insulin infusions can lead to severe hypophosphatemia, mainly as a result of intracelluar phosphate shifting [198-201]. Hypophosphatemia can be resulted with rhabdomyolysis. Other risk factors for rhabdomyolysis are severe hyperglycemia and high osmolality. But the pathogenic mechanism leading to rhabdomyolysis in DKA remains unclear. There are few reported cases in literature which had rhabdomyolysis in DKA. There may be no symp‐ toms or the condition can present with a mild increase of creatine kinase or rarely significant

In DKA treatment, patients may require central vascular access for intensive fluid re‐ placement. However, this route of vascular access causes many complications [206] like venous thromboembolism (VTE) [207]. Children with thrombophilia, malignancy, congen‐ ital cardiac disease, acute infection, trauma and surgery have a high risk for complica‐ tions of central venous catheter (CVC) related VTE [206]. In the medical literature there have been few reported cases CVC related VTE in DKA children without known risk factors. [208-210]. Thus, DKA and its treatment may promote a prothrombotic state and activation of vascular endothelium, predisposing to thrombosis. Whilst, DKA has not been identified as an isolated risk factor for CVC-related VTE in adults [211]. Where es‐ sential for, intensive fluid replacement in DKA, these lines should be removed as soon as possible, particularly as CVC-related VTE appears to occur within the first 24-48

Acute pancreatitis is a well known complication of DKA in adults [212] but is unusual in childhood. In children with DKA, abdominal pain and vomiting are common. In addi‐ tion to this, patients with DKA also have elevated serum pancreatic enzyme (amylase/ lipase) concentrations without clinical signs or symptoms and without radiographic evi‐ dence of pancreatitis [213,214]. Although hypertriglyceridemia is a known cause of acute pancreatitis and elevated triglyceride concentrations are frequent during DKA, an associ‐ ation between elevated triglyceride concentrations in DKA and pancreatic enzyme eleva‐ tion or pancreatitis have not be showned in the previous studies [213,215]. The mechanism responsible for pancreatic enzyme elevation in DKA has thus remained un‐ clear. Physicians should be aware of this phenomenon so that patients with DKA who have abdominal pain and elevated pancreatic enzymes are not erroneously diagnosed with acute pancreatitis unless in the presence of persistent abdominal pain, which does Mucormycosis is an acute, rapidly progressing, and often fatal facultative fungal infection occurs in patients with diabetes who have poor glycemic control and DKA, which have been well established as predisposing factors for fungal growth. Mucormycosis can be classfied; cutaneous, rhino-cerebral, pulmonary, gastrointestinal, central nervous system and dissemi‐ nated [216]. The rhino-cerebral forms develops in patients with diabetes, particularly with the complication such as DKA. The most common symptoms are; facial pain, headache, fe‐ ver, and mental obtundation [217]. In the Figure 4 there is a patient of us, firstly diagnosed T1DM with DKA infected by mucormycozis [218].

**Figure 4.** A 15 years old male patient firstly diagnosed T1DM with DKA infected by rhino-orbita-cerebral mucormyco‐ zis (Picture from the reference [218])

#### **7.6. Pulmonary oedema**

Pulmonary oedema is a rare, iatrogenic complication of DKA. Usually occurs within a few hours of initiation of treatment related with rapid infusion of crystalloids over a short peri‐ od of time. Elderly patients and those with impaired cardiac/renal function are at high risk and monitoring of central venous pressure should be considered [219].

#### **7.7. Pneumomediastinum**

Spontaneous pneumomediastinum is a rare pulmonary complication of DKA [220]. Kuss‐ maul breathing and repeated vomiting increases the intra-alveolar pressure; that leads to alveolar rupture; then, the air penetrates peribronchial and perivascular spaces and reach the mediastinum. Extension into neck and subcutaneous tissue could be seen. The most common sypmtoms include chest pain and dyspnoea. Treatment is mostly supportive; management of nausea/vomiting along with correction of acidosis to break Kussmaul breathing is should be considered. Patients should be carefully monitored in intensive care settings [221-223].

To prevent the development CE the following should be made; avoiding excessive hy‐ dration and rapid reduction of plasma osmolarity, a gradual decline in serum glucose and maintenance of serum glucose between 250–300 mg/dl until the patient's mental sta‐

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First of all the rate of fluid administration should be decreased and head of the bed lifted up [236]. Administration of IV mannitol in a dosage of 1.0 g/kg over 20 minutes when repeated as necessary in 1-2 hours shows an improvement in clinical outcome [224,227,228,239]. Pa‐ tients who do not respond adequately to mannitol of a dose of 1 g/kg, 5-10 mL/kg 3% saline

Neurologic collapse during DKA can cause other intracerebral complications, with or with‐ out associated edema, but defined not idiopathic CE [227]. These include; subarachnoid hemorrhage, basilar artery thrombosis [224], cerebral venous thrombosis [241,242], menin‐

DKA can be prevented by access to a 24-hours telephone helpline for emergency advice and treatment, sufficient patient education and easier access to medical care. Especially patients should be educated about a clinical condition which increases the risk of developing DKA

**2.** Early contact with a 24-hours telephone helpline or the health care provider should be

**4.** Patients should be advised never to discontinue insulin before contact with health care

**5.** Patients should be informed about blood glucose goals, the use of additional dose short or rapid acting insulin and the medications available to suppress a fever and treat an

**6.** In the case of nause and vomiting an easily digestible liquid diet containing carbohy‐

**7.** Family members should be educated about sick day management and record keeping including assessing and documenting temperature, blood glucose, and urine/blood ke‐

**1.** Patients should be educated about what are the precipitating factors of DKA.

**3.** The importance of insulin during an acute illness should be emphasized.

tone testing, insulin administration, oral intake and weight [93].

goencephalitis [243] and disseminated intravascular coagulation [244,245].

tus is improved [238].

**8. Preventıon**

provider.

infection.

infusion is an alternative treatment [240].

**7.9. Intracerebral complications other than CE**

and the changes in the treatment at this situations.

These are includes the following;

obtained in an acute illness.

drates and salt should be initiated.

#### **7.8. Cerebral edema**

Symptomatic cerebral edema (CE) is rare in adults treated for DKA, although asympto‐ matic CE may be occur [224] and may be present before treatment [225]. In contrast to this, CE occurs in ~0.3–1.0% of DKA episodes in children [224,226) and is associated with a mortality rate of 20–40% [226] and accounts for 57–87% of all DKA deaths [224,226]. Because of possible delay in diagnosis and more susceptibility to metabolic and vascular changes, children <5 years of age have higher risk for the development of CE. The recog‐ nized risk factors for development of CE are acidosis, hypocapnia and elevated serum urea nitrogen (indicator of severity of ketoacidosis and dehydration) [227]. The etiology of CE is unknown; many mechanisms have been proposed including cerebral hypoperfu‐ sion with subsequent re-perfusion [228,229], the generation of various inflammatory me‐ diators [230], increased cerebral blood flow, disruption of cell membrane ion transport and a rapid shift in extracellular and intracellular fluids resulting in changes in osmolali‐ ty. Thus the etiology of DKA-related CE is multifactorial and results of an interplay of complex pathophysiological processes involving the brain [231-235]. The time of onset is not the same in all affected individuals; two-thirds of patients develops signs and symp‐ toms in the first 6-7 hours and the rest from 10-24 hours after start of the treatment with the early-onset individuals tending to be younger [182,236,237].

Muir et al. suggested a model for early detection. The system allowed 92% sensitivity and 96% specificity for the recognition of CE early enough for intervention. One diagnostic crite‐ rion, two major criteria or one major plus two minor criteria is suitable to establish CE [236]. Diagnostic criteria, major criteria and minor criteria are shown in Table 6.


**Table 6.** Diagnostic criteria, major criteria and minor criteria for Cerebral Edema

To prevent the development CE the following should be made; avoiding excessive hy‐ dration and rapid reduction of plasma osmolarity, a gradual decline in serum glucose and maintenance of serum glucose between 250–300 mg/dl until the patient's mental sta‐ tus is improved [238].

First of all the rate of fluid administration should be decreased and head of the bed lifted up [236]. Administration of IV mannitol in a dosage of 1.0 g/kg over 20 minutes when repeated as necessary in 1-2 hours shows an improvement in clinical outcome [224,227,228,239]. Pa‐ tients who do not respond adequately to mannitol of a dose of 1 g/kg, 5-10 mL/kg 3% saline infusion is an alternative treatment [240].

#### **7.9. Intracerebral complications other than CE**

Neurologic collapse during DKA can cause other intracerebral complications, with or with‐ out associated edema, but defined not idiopathic CE [227]. These include; subarachnoid hemorrhage, basilar artery thrombosis [224], cerebral venous thrombosis [241,242], menin‐ goencephalitis [243] and disseminated intravascular coagulation [244,245].
