**2. Diabetic ketoacidosis and cerebrovascular accidents**

Although cerebrovascular accidents represent a significant and well-known precipitating factor for DKA, the literature data on precise mechanisms, distinctive features or manage‐ ment guidelines for patients are quite few or missing. The prevalence of stroke as the precip‐ itating factor for DKA was 0% in some studies [40] to as much as 7% in others [24]. Considering the data from the recent study in USA, most of the DKA patients (e.g. 80%) were in the age 18-65 years, with only 18% younger than 18; even 24% of all patients with DKA were in the age 45-65 years [32] Based on these data, it seems that the prevalence of DKA in patients with stroke may be underestimated and its importance under-appreciated in many cases.

**DKA STROKE COMMENTS**

**Increased or decreased breathing frequency**, abnormal breathing patterns, Cheyne-Stokes type

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial

**Dry skin Skin may be dry**, or moisture A dehydration may occur in

sometimes low

High blood sugar level High sugar level in diabetics Due to the effect of counter-

Blood glucose levels are high in the majority of diabetic patients suffering stroke. Moreover, pH, bicarbonate and anion gap are not routinely monitored in all diabetic patients suffering stroke, at least not in secondary level health institutions worldwide. In conclusion, some of

Furthermore, there is striking lack of literature data concerning management of adult dia‐ betic patients with stroke. Although there are clear concerns about the volume overload, in‐ tensive use of osmotic and Henley's loop diuretics and the need for careful volume and monitoring in patients suffering cerebrovascular accident and DKA no clear guidelines were

uncommon

High ketone level in serum and urine Moderately high ketone level in urine

Low serum (<15 mmol/l) bicarbonate Serum bicarbonate usually normal

the DKA cases in patients with stroke may easily be overlooked.

produced for intensive care units and intensive care neurologic units.

**Table 2.** Symptoms and signs in diabetic ketoacidosis and stroke: the overlapping features

Low (<7.3) plasma pH Plasma pH usually normal

Increased ( >/12) anion gap Anion gap usually >/12

Different kinds of breath odor not

in diabetics, alcohol abuse, starvation

Breathing patterns may be similar and interchangeably assigned to either of the diseases stroke the clinical

Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 319

case of not having access to water or fluids, or intensive use

Fruity scented breath may be hardly recognizable. Moreover, the odor appearing after ingestion of various sweet and fruits may imitate the characteristic odor of DKA

regulatory hormones

of osmotic diuretics

examination

Abdominal pain Headache

**A generally ill appearance A generally ill appearance**

**Dry mouth, Often dry mouth Increased heart rate, Increased heart rate** Low blood pressure Mainly high blood pressure,

Shortness of breath,**increased rate of**

A distinctive fruity odor on the breath,

fruity-scented breath

**breathing** -Kusmaul's type

Cerebrovascular accidents lead to increased release of counter-regulatory hormones (cate‐ cholamines, cortisol) which lead to hyperglycemia. Hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glu‐ cose utilization by peripheral tissues. Also these hormones increase the release of free fatty acids from peripheral tissues and their utilization as the energy source in hepatic and mus‐ cle mitochondria (beta-oxidation) with the increased ketone production as the direct conse‐ quence. This sequence is identical to the one seen in acute myocardial infarction [32], [19].

There is a significant overlapping of the symptoms in stroke and DKA (table 2). One can as‐ sume that an interference of symptoms of the two conditions during the clinical examination may be confusing and their interpretation difficult particularly in elder and less communica‐ tive patients.


Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 319

**2. Diabetic ketoacidosis and cerebrovascular accidents**

in many cases.

318 Type 1 Diabetes

tive patients.

Although cerebrovascular accidents represent a significant and well-known precipitating factor for DKA, the literature data on precise mechanisms, distinctive features or manage‐ ment guidelines for patients are quite few or missing. The prevalence of stroke as the precip‐ itating factor for DKA was 0% in some studies [40] to as much as 7% in others [24]. Considering the data from the recent study in USA, most of the DKA patients (e.g. 80%) were in the age 18-65 years, with only 18% younger than 18; even 24% of all patients with DKA were in the age 45-65 years [32] Based on these data, it seems that the prevalence of DKA in patients with stroke may be underestimated and its importance under-appreciated

Cerebrovascular accidents lead to increased release of counter-regulatory hormones (cate‐ cholamines, cortisol) which lead to hyperglycemia. Hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glu‐ cose utilization by peripheral tissues. Also these hormones increase the release of free fatty acids from peripheral tissues and their utilization as the energy source in hepatic and mus‐ cle mitochondria (beta-oxidation) with the increased ketone production as the direct conse‐ quence. This sequence is identical to the one seen in acute myocardial infarction [32], [19].

There is a significant overlapping of the symptoms in stroke and DKA (table 2). One can as‐ sume that an interference of symptoms of the two conditions during the clinical examination may be confusing and their interpretation difficult particularly in elder and less communica‐

**DKA STROKE COMMENTS**

**Frequent urination Incontinence** Frequent urination and

weakness in one arm / leg

**Loss of appetite Loss of appetite** Loss of appetite in DKA results

incontinence may be difficult to differentiate in a somnolent/

from predominantly catabolic pattern of metabolism, nausea

Mental status changes can be seen with mild-to-moderate DKA; more severe deterioration in mental status is typical with moderate-to-severe DKA.

comatose patient

and confusion

Excessive thirst or drinking lots of fluid Inability to swallow

**General weakness General weakness**, a feeling of

**Confusion, somnolence, stupor, comma Confusion, somnolence, stupor,**

**comma**

**Nausea and vomiting Nausea and vomiting**


**Table 2.** Symptoms and signs in diabetic ketoacidosis and stroke: the overlapping features

Blood glucose levels are high in the majority of diabetic patients suffering stroke. Moreover, pH, bicarbonate and anion gap are not routinely monitored in all diabetic patients suffering stroke, at least not in secondary level health institutions worldwide. In conclusion, some of the DKA cases in patients with stroke may easily be overlooked.

Furthermore, there is striking lack of literature data concerning management of adult dia‐ betic patients with stroke. Although there are clear concerns about the volume overload, in‐ tensive use of osmotic and Henley's loop diuretics and the need for careful volume and monitoring in patients suffering cerebrovascular accident and DKA no clear guidelines were produced for intensive care units and intensive care neurologic units.

Some of the management guidelines may be defined here:

**1.** It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration poten‐ tates a tendency toward intravascular thromboembolism. Since the use of osmotic and sometimes also other kinds of diuretics is inevitable in patients with stroke a careful hy‐ dration is recommended in order to avoid further thrombotic complications.

the cerebral metabolic state worsen. After initiation of DKA therapy, abnormalities in Pro‐ tein C, Protein S, plasma homo-cysteine, and von Willebrand Factor (vWF) were demon‐ strated [11, 9]. While protein C levels normalize with treatment, free protein S, the active

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial

Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 321

Arterial ischemic stroke [47], cerebral venous thrombosis [29], and hemorrhagic stroke [36] were noted in children following DKA. DKA-associated cerebral edema may also predis‐ pose to ischemic injury and hemorrhage, though cases of stroke without concomitant cere‐ bral edema have been identified [49]. As stroke itself may cause cerebral edema, it becomes difficult to ascertain whether cerebral edema in DKA is the cause or an effect of acute cere‐ bral infarction. A sub-arachnoid or intra-ventricular hemorrhage may occur without cere‐ bral edema as was demonstrated using on CT scanning. Clinically, a transcranial Doppler ultrasound in children with DKA demonstrated significant vascular dysregulation with vas‐ odilation, decreased cerebral blood flow velocity, and loss of normal cerebral blood flow regulation that only normalized after treatment. Another group of researchers found normal to increased cerebral blood flow with impaired cerebral auto-regulation during episodes of

Treatment with bumetanide, [27] an inhibitor of Na-K-2Cl Co-transport, resulted in im‐ provements in metabolic measures during untreated DKA and amelioration of the declines

It is clear that at least some of these mechanisms may be operative in adult DKA. Abnormal‐ ities in coagulation during DKA or its treatment have been also noted in adults. Indeed, an endothelial injury, platelet activation, relative hypo-fibrinolysis, and activation of the coagu‐ lation system [20] even in the absence of clinical signs of thrombosis were all demonstrated in patients with DKA. However, the up-regulation was not to a degree expected for the in‐ crease in coagulation activity (thrombin-antithrombin III complex and prothrombin frag‐

In summary, cerebrovascular accidents represent a significant and well-known precipitating factor for DKA. It seems that the prevalence of DKA in patients with stroke may be underes‐

It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration potentates a ten‐ dency toward intravascular thromboembolism. Unfortunately, like in acute myocardial in‐ farction, the volume replenishment capacity in patients with stroke is often limited. Intravenous insulin and monitoring and correction of possible electrolyte imbalances are the

Not only does stroke precipitate DKA, but the vice-versa is also true: diabetic ketoacidosis itself was reported to be a risk factor for the occurrence of stroke in children and youth. A cerebral hypo-perfusion occurs in untreated DKA and may lead to cerebral injury. Arterial ischemic stroke, cerebral venous thrombosis and hemorrhagic stroke were noted following

anticoagulant of protein S, is reduced and does not return to baseline with treatment.

DKA not associated with overt CE in 6 children [20].

in metabolic measures during initial DKA treatment.

timated and its importance under-appreciated in many cases.

ment 1 + 2 levels) at DKA presentation.

mainstay of the treatment.

DKA episodes.


Not only does stroke precipitate DKA, but the vice-versa is also true [20]: diabetic ketoacido‐ sis itself was reported as a risk factor for the occurrence of stroke in children and youth. The risk of acute ischemic or hemorrhagic stroke during the acute DKA episode is perhaps un‐ der-appreciated.

Systemic inflammation is present in DKA, with resultant vascular endothelial perturbation that may result in coagulopathy and increased hemorrhagic risk. Hyperglycemia and acido‐ sis may contribute to oxidative injury [25], as well as ischemic injury [34]. Thrombotic risk during DKA is also elevated by abnormalities in coagulation factors, platelet activation, blood volume and flow, and vascular reactivity.

Recent data demonstrate that DKA is associated with reduced cerebral blood flow and with brain cell swelling [23]. These data suggest that cerebral injury resulting from DKA may be similar to hypoxic/ischemic brain injury. A cerebral hypo-perfusion occurs in untreated DKA. [23] In analogy with ischemia/reperfusion injury, DKA could be associated with meta‐ bolic abnormalities similar to those of hypoxic/ischemic brain injury and that these abnor‐ malities would worsen during initial DKA treatment as normal cerebral perfusion is reestablished [15, 4].

Although a small percentage of children have clinically apparent cerebral injury at presenta‐ tion of DKA prior to treatment, neurological decline during DKA treatment is more com‐ mon [16]. During initial DKA treatment with insulin and intravenous saline, key aspects of the cerebral metabolic state worsen. After initiation of DKA therapy, abnormalities in Pro‐ tein C, Protein S, plasma homo-cysteine, and von Willebrand Factor (vWF) were demon‐ strated [11, 9]. While protein C levels normalize with treatment, free protein S, the active anticoagulant of protein S, is reduced and does not return to baseline with treatment.

Some of the management guidelines may be defined here:

use of diuretics may precipitate pro-thrombotic state.

may be a precipitating factor for stroke (see later)

sium levels or performing potassium substitution

blood volume and flow, and vascular reactivity.

der-appreciated.

320 Type 1 Diabetes

reestablished [15, 4].

**5.** Bicarbonate therapy is not recommended except in extreme acidosis.

**1.** It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration poten‐ tates a tendency toward intravascular thromboembolism. Since the use of osmotic and sometimes also other kinds of diuretics is inevitable in patients with stroke a careful hy‐

**2.** Fluid resuscitation must be performed carefully, in small aliquots, and with constant monitoring of blood pressure, hematocrit and plasma sodium; novel minimal invasive procedures [39] should have advantages over central venous catheter since CVP itself was reported to be a risk factor for cerebrovascular thromboembolism [33]. Excessive

**3.** Infused insulin is the principle therapeutic tool for fighting DKA in patients with cere‐ brovascular accidents. Since fluid resuscitation must be restricted, DKA itself is expect‐ ed to have more prolonged clinical course. This may be of importance, since DKA itself

**4.** Serum potassium must be carefully monitored in all cardiovascular patients with DKA (see earlier). Hyper or hypokalemia should be promptly corrected; thus said, insulin-in‐ duced intracellular shift of potassium must be taken in account when evaluating potas‐

Not only does stroke precipitate DKA, but the vice-versa is also true [20]: diabetic ketoacido‐ sis itself was reported as a risk factor for the occurrence of stroke in children and youth. The risk of acute ischemic or hemorrhagic stroke during the acute DKA episode is perhaps un‐

Systemic inflammation is present in DKA, with resultant vascular endothelial perturbation that may result in coagulopathy and increased hemorrhagic risk. Hyperglycemia and acido‐ sis may contribute to oxidative injury [25], as well as ischemic injury [34]. Thrombotic risk during DKA is also elevated by abnormalities in coagulation factors, platelet activation,

Recent data demonstrate that DKA is associated with reduced cerebral blood flow and with brain cell swelling [23]. These data suggest that cerebral injury resulting from DKA may be similar to hypoxic/ischemic brain injury. A cerebral hypo-perfusion occurs in untreated DKA. [23] In analogy with ischemia/reperfusion injury, DKA could be associated with meta‐ bolic abnormalities similar to those of hypoxic/ischemic brain injury and that these abnor‐ malities would worsen during initial DKA treatment as normal cerebral perfusion is

Although a small percentage of children have clinically apparent cerebral injury at presenta‐ tion of DKA prior to treatment, neurological decline during DKA treatment is more com‐ mon [16]. During initial DKA treatment with insulin and intravenous saline, key aspects of

dration is recommended in order to avoid further thrombotic complications.

Arterial ischemic stroke [47], cerebral venous thrombosis [29], and hemorrhagic stroke [36] were noted in children following DKA. DKA-associated cerebral edema may also predis‐ pose to ischemic injury and hemorrhage, though cases of stroke without concomitant cere‐ bral edema have been identified [49]. As stroke itself may cause cerebral edema, it becomes difficult to ascertain whether cerebral edema in DKA is the cause or an effect of acute cere‐ bral infarction. A sub-arachnoid or intra-ventricular hemorrhage may occur without cere‐ bral edema as was demonstrated using on CT scanning. Clinically, a transcranial Doppler ultrasound in children with DKA demonstrated significant vascular dysregulation with vas‐ odilation, decreased cerebral blood flow velocity, and loss of normal cerebral blood flow regulation that only normalized after treatment. Another group of researchers found normal to increased cerebral blood flow with impaired cerebral auto-regulation during episodes of DKA not associated with overt CE in 6 children [20].

Treatment with bumetanide, [27] an inhibitor of Na-K-2Cl Co-transport, resulted in im‐ provements in metabolic measures during untreated DKA and amelioration of the declines in metabolic measures during initial DKA treatment.

It is clear that at least some of these mechanisms may be operative in adult DKA. Abnormal‐ ities in coagulation during DKA or its treatment have been also noted in adults. Indeed, an endothelial injury, platelet activation, relative hypo-fibrinolysis, and activation of the coagu‐ lation system [20] even in the absence of clinical signs of thrombosis were all demonstrated in patients with DKA. However, the up-regulation was not to a degree expected for the in‐ crease in coagulation activity (thrombin-antithrombin III complex and prothrombin frag‐ ment 1 + 2 levels) at DKA presentation.

In summary, cerebrovascular accidents represent a significant and well-known precipitating factor for DKA. It seems that the prevalence of DKA in patients with stroke may be underes‐ timated and its importance under-appreciated in many cases.

It is important that patients with stroke complicated by DKA avoid dehydration since both DKA and stroke correlate with the pro-thrombotic state and dehydration potentates a ten‐ dency toward intravascular thromboembolism. Unfortunately, like in acute myocardial in‐ farction, the volume replenishment capacity in patients with stroke is often limited. Intravenous insulin and monitoring and correction of possible electrolyte imbalances are the mainstay of the treatment.

Not only does stroke precipitate DKA, but the vice-versa is also true: diabetic ketoacidosis itself was reported to be a risk factor for the occurrence of stroke in children and youth. A cerebral hypo-perfusion occurs in untreated DKA and may lead to cerebral injury. Arterial ischemic stroke, cerebral venous thrombosis and hemorrhagic stroke were noted following DKA episodes.

Treatment with bumetanide, an inhibitor of Na-K-2Cl co-transport, resulted in improve‐ ments in metabolic measures during untreated DKA and prevented cerebral metabolic ag‐ gravation during initial DKA treatment.

However, even the severe symptoms may be hardly recognizable for they can mimic those of the underlying disease – e.g. DKA itself. Hipophosphatemia may be the cause of rhabdo‐ myolysis, which (though not often) can lead to occurrence of cardiomyopathy and acute re‐

Distinctive Characteristics and Specific Management of Diabetic Ketoacidosis in Patients with Acute Myocardial

Infarction, Stroke and Renal Failure http://dx.doi.org/10.5772/ 52390 323

Even after initiation of phosphate replacement, serum phosphate levels are often difficult to normalize, and a severe metabolic acidosis can last despite insulin-induced normalization of

In cases of severe acidosis, phosphate replacement is of paramount importance [31]. Howev‐ er, after initial-phase phosphate replacement, the re-institution of acid-base balance phos‐ phate re-shifts from intra- to extracellular space; this can lead to the hyperphosphataemia later in the course of treatment [13]. Therefore, serum phosphate levels should be monitored continuously. With the occurrence of acute renal failure, indications for haemodialysis in‐ clude oliguria, persistent metabolic acidosis resistant to standard therapy, fluid overload and hypertension. Early initiation of haemodialysis is not only effective against the direct consequences of acute renal failure - uremia and hypervolemia – but also contribute to rapid correction of metabolic acidosis and hypophosphatemia [28]. Indeed, the existing hypophos‐ phataemia is easily corrected once a normal acid-base balance is established by haemodialy‐ sis. Prompt institution of dialysis is important as the diabetic patient may tolerate uraemia less well. Uncontrolled ketosis may worsen hyperkaliemia and metabolic acidosis. Insulin requirements may be increased due to insulin resistance, or decreased due to impaired

The vast majority of patients require intermittent haemodialysis. Patients with cardiac dys‐ function or autonomic neuropathy tend to develop hypotension during treatment. Also, an‐ ticoagulation with heparin may increase the risk of hemorrhage from proliferative retinopathy, therefore prostacyclin may be a safer alternative [52]. Peritoneal dialysis may be complicated by peritonitis and chest infections. Also, haemodialysis allows greater fluid

Despite the strong prevalence of compromised immune status, constant state of protein mal‐ nutrition, frequent vascular accessing with a predisposition to significant infections, in‐ creased incidence of cardiovascular diseases, the occurrence of DKA in patients with chronic renal failure is quite rare. [41, 3]. Kidneys play a major role in insulin breakdown [38]; ad‐ vanced chronic renal failure is associated with both insulin resistance and decreased insulin degradation. The latter may lead to a marked decrease in insulin requirement. Therefore, many patients see an improvement in glycemic control when they progress to haemodialy‐ sis. Furthermore, in hyperglycemic dialysis-dependent patients volume contraction due to osmotic diuresis is not encountered. Since glycosuria and osmotic diuresis account for most of the fluid and electrolyte losses seen in DKA, anuric patients may be somewhat protected from dehydration. However they may still be prone to development of hyperkalemia and metabolic acidosis [37]. In persistent and long-lasting DKA, a substantial volume loss can

removal and remove restrictions for administration of drugs and nutrition [56].

nal failure.

blood glucose.

clearance of circulating insulin [38, 56].

**3.2. Diabetic ketoacidosis and chronic renal failure**
