Cardio Diabetes_2017 book

228 Congestive Heart Failure in Diabetic...!
How it is Different?

left ventricular filling pressures, less exercise toler- and macrophage infiltration than tissue from patients
ance and more need for hospitalization without DM. and impaired platelet aggregation and
adhesion wtih consequent higher risk of thrombo-
PATHOPHYSIOLOGY sis. Angiographic examination of patients with DM
and unstable angina has shown a higher incidence
The pathophysiological basis of the relationship be- of plaque ulceration and intracoronary thrombus for-
tween CHF and DM may involve several possible mation than subjects without DM.
scenarios, that further potentiate each other (figure 1)
Results from the Framingham heart study demon-
DM may increase the risk of CHF through in- strated that patients with DM are at increased risk of
creased risk for CAD and subsequent progression developing CHF following myocardial infarction with
to post-ischemic CHF. In addition, DM may induce worse outcome compared to non-diabetic patients
myocardial alterations directly altering cardiac struc-
ture and function. (diabetic cardiomyopathy) (13) Finally CONGESTIVE HEART FAILURE INDUCED
CHF may induce insulin resistance and the subse- Type 2 Diabetes
quent progression to DM.
Congestive heart failure (CHF) is an insulin-resistant
Post-ischemic Congestive Heart Failure in sate which constitutes the main risk factor for the
Diabetes: development of non-insulin dependent diabetes mel-
litus (NIDDM)
Patient with DM show a 2-4 fold increase in the rela-
tive risk of cardiovascular (CV) morbidity and mortali- CHF was associated with NIDDM independent of age,
ty compared to non-diabetic subjects.(14) In a Finnish sex age, family history of diabetes, body mass index,
population-based study, the risk of acute myocardial (BMI) waist / hip ratio,, and diastolic blood pressure.
infarction was 7-fold greater in patient with DM com- When untreated CHF patients where grouped into
pared to patients without a DM. suggesting that DM those with low (I and II) and high (III & IV)
is a CV risk equivalent
New York Heart Association (NYHA) classes, the as-
The pathophysiological basis for these adverse out- sociation of CHF and NIDDM was stronger with the
comes involves the hyperglycaemic milieu that exac- worsening of CHF .The mechanisms underlying this
erbates concomitant CV risk factors such as hyper- association are not fully understood, Sympathetic
tension dyslpidemia and activation of neurohormonal nervous system overactivity and consequent lipoly-
and inflammatory mechanisms resulting in accelerat- sis, activation of the renin–angiotensin-aldosterone
ed and more extensive CAD system (RAAS) and increased cytokine production
in CHF might play a roll in the development of insu-
Epidemiological studies show that subjects with insu- lin–resistance and consequent progression to type 2
lin resistance have an increased risk of incident CAD DM. CHF. may induced insulin resistance and in turn
even in the absence of overt DM . triggers CHF in a vicious cycle..

Insulin resistance and consequent compensatory hy- CONGESTIVE HEART FAILURE INDUCED
perinsulinemia is an early and central defect in the BY CARDIOMYOPATHY
natural history of type 2 DM that may precede its
diagnosis by 10-20years. This defect is insulin ac- Patients with DM may develop a unique form of
tion, is associated with a cluster of abnormalities cardiac alterations termed diabetic cardiomyopathy,
referred to as the insulin resistance syndrome (or defined as a defect in ventricular contractile function
metabolic syndrome) that contributes to endothe- that is independent of CAD and hypertension. The
lial dysfunction and progression toward advanced term diabetic cardiomyopathy describes myocardial
atherosclerosis. Diabetes mellitus is arteriopathic changes induce by diabetes – associated defects: in-
through a number of mechanisms. There include sulin-resistance and hyperglycemia which are central
reduced vascular nitric oxide reduced prostacycline drivers in several adaptive and maladaptive respons-
production and enhanced endothelin, angiotensin II, es ultimately inducing specific detrimental myocyte
tissue factor activity and platelet activity. abnormalities. several synergistic pathological mech-
anism have been investigated as determinants of di-
When overt DM occurs hyperglycemia induced oxi- abetic cardiomyopathy .
dative stress may lead to a prothrombolic and proin-
flammatory state favouring the propensity to plaque
complications. Coronary tissue from patients with
DM exhibits a larger content of lipid-rich atheroma

GCDC 2017

Cardio Diabetes Medicine 2017 229

METABOLIC ALTERATIONS: IMPAIRED CALCIUM HOMEOSTASIS:

One of consequences of. Insulin- resistance is the DM is associated with ab-normalites in calcium han-
impaired hormone capacity to inhibit adipose issue dling major changes in DM include a shift in myocin
lipolysis with consequent enhanced free fatty acid isoenzyme composition (from V1-V3 isoforms) and
(FFA) release particularly in subject with visceral the predominance of the fetal (beta) myosin heavy
adiposity, and the reduction in myocardial glucose chain expression with respect to the (alpha) myocin
transporter GLUT-4. Expression and glucose uptake, heavy chain ,leading to depressed ATP ase activity
These metabolic alterations may be firstly related of myofibrils and reduced contractile force. In addi-
to changes in substrate availability (higher availabil- tion, alterations in sarco-endoplasmic reticulum Ca2+
ity FFA and insulin resistant-mediated impairment ATPase (SERCA) 2 activity, inefficient sequestration
in myocyte glucose metabolism) and lead to a shift of Ca2 + in the sacroplasmic reticulum resulting in
from glucose to FFA uptake and utilization in the Ca2 + overload in the cystosol and defects in ryano-
heart (13) dine, receptors activity have been proposed as major
determinants of impaired relaxation and contractile
This metabolic subtract changes lead to dysfunction dysfunction. Recently, a perturbation in the function
of myocardial mitochondria with increased genera- of the endoplasmic reticulum, a central organelle en-
tion of reactive oxygen species promoting mitochon- trusted with Ca2 +haemeostasis and protein folding
drial uncoupling and leading to increase oxygen con- and maturation has been suggested as the leading
sumption and reduced myocardial efficiency cause of myocytes apoptosis .

Diabetic mitochondrial dysfunction is sustained by HYPERGLYCEMIA INDUCED
ultrastructural changes (e.g., hyperplasia, reduced ALTERATIONS
organelle size, loss of membranes and cristae) and
reduced expression of genes involved in oxidative Hyperglycemia is one of the main pathogenic mech-
phosphorylation .The phoscreatine / ATP ratio, a anism leading to diabetic structural alteration in CHF.
surrogate marker of mitochondrial function and car- Important consequences of hyperglycemia- induced
diac energetic, is significantly reduced in patient cellular injury are the function of AGE – advanced gly-
with type I and type. 2 DM without a known history cation end products resulting from the non-enzymat-
of CAD,, and correlates with the degree of diastolic ic glycation and oxidation of proteins and lipids, and
dysfunction these metabolic alterations\ characterize the activation of the protein kinase C AGE accumula-
the early stages of diabetic cardiomyopathy without tion in DM is known to induced myocardial alteration
overt functional alteration. As metabolic alterations primarily via two mechanisms. Advanced glycations
become long standing, high FFA levels activate myo- end-product form cross – links within or between
cyte expression of peroxisome proliferator-activated proteins such as myocardial collagen, laminin and
receptor (alpha) that stimulates the transcription of elastin, thereby impairing the ability of collagen to
multiple genes responsible for an increase in mito- be degraded,, leading to collagen accumulation and
chondrial (FFA) transport and oxidation. FFA myo- fibrosis with increased myocardial stiffness and im-
cardial uptake may exceed FFA oxylation capacity paired cardiac relaxation. Secondly, soluble extra
leading to triglycerides accumulation in the myocytes cellular advanced glycated end-products bind to
(lipotoxicity) and production of toxic lipid intermedi- their receptors stimulating the upregulation of trans-
ates such as diacylglycerol and ceramides both pro- forming growth factor-and important pro-sclerotic
moting oxidative stress and cardiomyocytes apop- factor that have also been implicated in inflammatory
tosis with consequient mechanical dysfunction and signaling pathways .
organ failure.
Hyperglycaemic–induced protein kinase C activation
There are some data to suggest that the risk of heart also contributes to cardiac fibrosis by stimulating
failure could be lessened connective tissue growth factor expression

By tight control of HBA1c, Lind and colleagues The activation of all the above hyperglycaemic – in-
demonstrated that patient with a HBA1c of at least duced pathways characterise the middle stage of di-
10.5% had a four – fold greater risk of heart failure abetic cardiomyopathy associated with myocellular
than did those with a HBA1c of less than 6.5% . How- hypertrophy and myocardial fibrosis which contrib-
ever, strict glycemic control has not uniformly been ute to abnormal diastolic dysfunction and normal or
demonstrated to reduce the onset of heart failure slightly decreased EF.

Cardio Diabetes Medicine

230 Congestive Heart Failure in Diabetic...!
How it is Different?

Renin Angiotensin Aldosterone system imbalance toward higher relative sympathetic drive .
activation
Sympathetic over activity is a common future in DM
DM is associated with the activation of the RAAS and CHF.. In non-diabetic CHF, sympathetic activa-
with consequent over production of angiotensin II, tion occurs in the later CHF stages leading to insulin
which contributes to heart fibrosis by stimulating ex- resistance, where as cardiac autonomic neuropathy
tra cellular matrix component synthesis, apoptosis/ is a central determinant of the diabetes induced mi-
proliferation, vascular inflammation and oxidative crovascular complication worsening metabolic and
damage. functional alteration in diabetic cardiomyopathy.. The
subsequent progression to CHF in turn, increases
Oxidative, Nitrosative and Nitrative stress. sympathetic activity. Increased cardiac sympathetic
activity, as already discussed, increases lipolysis,
Hyperglycemia –induced pathway activation even- FFA overflow influencing myocardial substrate utili-
tually results in the production of oxygen- derived zation,Mitochondrial uncoupling and oxidative stress
oxidants from both mitochondrial and non-mitochon- with consequent cardiac dysfunction, Cardiac auto-
drial sources. nomic neuropathy is also associated to a depressed
baroreflex function leading to impaired regulation of
A chronic increase in oxidative stress has several heart rate variability, stroke volume and blood pres-
harmful effect on the CV system by directly dam- sure that have been associated with both systolic and
aging proteins and DNA, by interfering with nitric diastolic dysfunction., Patients with severe cardiac
oxide production and by a modulation of intracellu- autonomic neuropathy may have distal sympathetic
lar, signaling pathways and proteins involved in the denervation associated with proximal ventricular is-
stimulated production of reactive oxygen species. Mi- lands of hyperinnervation that result in myocardial
tochondrial derived- reactive oxygen species appear regions that are unstable electrically. In the Action
to play the most crucial role as they can interact with to Control Cardiovascular Risk in Diabetes (ACCORD)
nitric oxide to form peroxynitrite species which at- trial, in which cardiac autonomic neuropathy was
tract various biomolecules leading (among other pro- strongly associated with all cause and CV disease
cesses) to the production of a modified amino acid, mortality independent of baseline CVD, DM duration,
nitrotyrosine, that can disrupt endothielial nitric oxide multiple traditional CV risk factors and medications .
synthase activity ultimately reducing nitric oxide bio-
availability and resulting in endothelial dysfunction. CLINICAL PHENOTYPES OF DIABETIC
HEART FAILURE
Disease of Small Cardiac Vessels
Diastolic dysfunction
Hyperglycemia is known to induce microangiopa-
thy, mainly through AGE formation characterized The most frequent and earliest functional abnormal-
by thickening of the capillary basement membranc ity in the diabetic heart is impaired diastolic compli-
and formation of micoaneurysms .These structur- ance, setting the stage for CHF with normal EF.(74).
al alterations cause functional modification such Although this alteration is not unique to DM. It has
as impaired nitric oxide production and permeabili- been detected in up to 75% of asymptomatic patient
ty of the endothelium with consequent endothelial with DM, it has been detected in upto 75% a symp-
dysfunction The consequent deficiency in coronary tomatic patients with DM. A small study provided in
blood flow reserve-contributes to loss of contractile sight into the phenotypic characteristics
proteins and myocyte necrosis with reactive focal
perivascular and interstitial fibrosis,. collagen depo- of patient with DM with LV diastolic dysfunction::40%
sition and hypertrophy of myocardial cells. had diastolic dysfunction, of which two third had im-
paired relaxation and one third pseudo- normaliza-
Cardiac Autonomic Neuropathy tion of mitral inflow on Doppler echocardiography.
Of note, patients with diastolic dysfunction were
Cardiac autonomic neuropathy is a common micro- young (mean age 43yrs), normotensive, and under
vascular complication of DM affecting a almost 17% good diabetic control,supporting the hypothesis that
of the patient with type 1 and 22% of those with type diastolic dysfunction. is an early feature in DM. The
2 DM The severity of hyperglycemia and DM duration development of diastolic dysfunction, found in both
are major determinants of cardiac autonomic neurop- systolic heart failure and HFpEF, though complex
athy, which leads to impaired regulation of CV func- and multifactorial, clearly it is a primary feature of
tion .An early manifestation of cardiac autonomic diabetic heart failure.
neuropathy is parasympathetic denervation with an

GCDC 2017

Cardio Diabetes Medicine 2017 231

SYSTOLIC DYSFUNCTION this later stage diabetic cardiomyopathy diabetic co-
morbidities such as hypertension dyslipidemia. Mi-
In the diabetic heart systolic dysfunctiuon is belived to crovascular dysfunction autonomic dysfunction and
be a later manifestaition of disease Usually ocurring renal impairment may accelerated the progression of
after the development of systolic dysfunction. cardiac dysfunction. Among hospitalized CHF patient
Recently the use of two dimensional speckle tracking those with DM tended to more to more frequently
echocardiography has shown the reasons of subclinical present with acute pulmonary edema or acute coro-
LV systolic dysfunction, measures as a decrease in nary syndrome CHF and renal impairment were the
LV longitudinal shortening in asymptomatic diabetic main determinants of outcome in patient with DM
patients with normal EF and assumed to have “isloated” and CAD and conversely DM is a potent indepen-
diastolic dysfunction., dent risk factor for motility in patients hospitalized
with CHF particularly in women. Glycemic control is
Subjects with type 2 DM are more susceptible to important prognostic factor as shown in a large co-
preclinical diastolic and systolic dysfunction com- hort of diabetic patients (25958) men and (22900)
pared to type 1 patients supporting a role of insulin women, in which each 1% increase in glycosylated
resistant mediated alterations in the determination of haemoglobin was associated with an 8% increased
early cardiac dysfunction and a possible protective risk of CHF .
role for insulin therapy. Diastolic dysfunction was
associated with the presence of mild complications HEART FAILURE SCREENING IN
of DM whereas systolic dysfunction was found in THE POPULATION WITH DIABETIC
the presence of more severe diabetic complications. MELLITUS
Suggesting that the extent of systolic dysfunction
may depend more on the magnitude and duration The higher morbidity and morality observed in pa-
of hyperglycemia tients with CHF and DM mandates its early identifi-
cations in order to initiate adequate treatments and
However in patients with DM the clear phelnotyp- delay disease progression. Currently there is no sin-
ic distinctions noted in experimental animal models gle imaging biomarker or histological finding pathog-
(marked hyperinsulinemia without hyperglycemia nomic for diabetic cardiomyopathy. In the studies of
leading to LV hypertrophy and systolic dysfunction left ventficular dysfunction (SOLVD) registry only
and hyperglycemia without hyperinsulinemia leading approximately half of the patients with an EF <45%
to systolic dysfunction.) have not been confirmed in had CHF symptoms making it difficult to screen only
patients with type I DM. Systolic dysfunction is less based on clinical grounds. Known independent risk
evident than in animal modes because these patients factors for CHF in diabetic patients are older age,
receive exogenous insulin, making them metabolical- Longer DM duration, visceral obesity, higher glyco-
ly similar to patients with type 2 DM. sylated haemoglobin and albuminuria making the
use of clinical characteristics to screen CHF in diabet-
Response to Stress Tests ic patients also difficult. Brain natriuretic peptite as a
screening toll showed a sensitivity of 92% and spec-
Latent LV dysfunction in diabetic heart, even in as- ificity of 72% for LV systolic dysfunction and it has
ymptomatic subjects with normal resting LV is dimen- been shown to be prognostically significant. Brain na-
sion and function, can be unmasked during exercise triuretic peptite level might therefore be considered
patient with type 2DM with normal myocardial func- a cost effective test with which to select patients
tion at rest but an abnormal response to exercise for echocardiographic evaluation but not sensitive
stress had significantly reduced longitudinal diastolic enough for early detection of pre-clinical myocardial
functional reserve index compared to those with a dysfunction Further more. plasma Brain natriuretic
normal stress response highlighting the important peptite levels have been found significantly higher is
role of myocardial diastolic relaxation in maintaining CHF patients with DM than in non-diabetic patients
normal myocardial function and exercise capacity at the same CHF score.
.These findings suggest that impaired cardiac per-
formance after exercise could be potential tool to The underlying mechanism for the higher Brain natri-
detect early contractile dysfunction in DM uretic peptide level in CHF patient with DM is not clear
propose mechanism include an increase in brain na-
HEART FAILURE PROJECTIONS AND triuretic peptide formation and or a decrease in deg-
PROGNOSIS radation due to hyperglycemia, cardiac autonomic
dysfunction or higher RAAS activation compared to
Long standing metabolic and functional alteration
ultimately lead to irreversible. Structural changes in

Cardio Diabetes Medicine

232 Congestive Heart Failure in Diabetic...!
How it is Different?

non-diabetic patients. Other biomarkers are of inter- hospitalization for cardiac causes, improve clinical
est class of biomarkers related to the synthesis and symptoms and cardiac function and simultaneously
are degradation of types I and III fibrillar collagens ameliorate LV remodelling.
(serum aminoterminal propeptide of type I and III ) the
most abundant collagens and in the myocardium and Ranolazine currently approved as an antianginal
associated with cardiac remodelling serum concen- agent reduced the Na-dependent Calcium overload
trations of the carboxy terminal propeptide of procol- via. Inhibition of the late sodium current (late Ina)
lagens type I were related to changes of LV filling channels and thus has been shown to improve di-
timings in patient with early type 2 DM Upregulation astolic tone and oxygen handling during myocardial
of matrics metalloproteinases lead to degeneration ischemia.AMP-activated protein kinase is found in
of the extracellular matris and replacement fibrosis abundance in the hart where it regulates the cellular
. Assays of these markers remain experimental and response to low energy states such as hypoxia and
need to be further validated in large trials. exercise to increase energy production.

Conventional echocardiographic techniques for as- CONCLUSIONS:
sessing LV hypertrophy are not specific for diabetic
cardiomyopathy. The development of new ultrasound DM and CHF are inter related conditions DM can af-
techniques such as echo strain imaging and the use fect cardiac structure and function in the absence
of magnetic resonance imaging for the evaluation of changes in blood pressure or CAD, a condition
of strain and strain rate have shown to be effective called diabetic cardiomyopathy. Insulin residence and
in the identification of subclinical LV systolic and hyperglycemia are central drivers of the initially adop-
diastolic dysfunction in asymptomatic patients with tive pathological but ultimately detrimental changes
DM and normal EF. Recently the European society occurring in diabetic cardiomyopathy. Alterations in
of cardiology has suggested criteria for the diagno- substrate utilization and mitochondrial dysfunction
sis of diastolic dysfunction. but there are no specific seem to be early and key alterations in diabetic car-
guidelines for CHF screening in the asymptomatic diomyopathy. In later stages concomitant CV risk
population with DM and recommendations for CHF factors such as hypertension, dyslipidemia neuro-
screening are warrented. A combination of clinical hormonal activation renal impairment and CAD may
characteristics potential symptoms biomarkers of further compromise cardiac dysfunction.
cardiac functions and new diagnostic technique may
provide potential tools to identify diabetes subject at Treatment of concomitant DM and CHF is challeng-
increased risk of developing CHF. The current ap- ing since many contemporaries therapics used for
proach to the classification of CHF emphasizes at tge DM are contraindicated or limited by comorbidities
development and progression of the disease from a such as renal dysfunction. Sub-group analysis of re-
Stage A Through D. Patients with DM who do not cent trials conducted in hospitalized.
yet demonstrate LV dysfunction would be considered
stage A . As patients move through stages B-D, they CHF patients with DM showed a different response
develop structural changes symptoms and then re- to standard medication being more prone to devel-
fractory and stage disease. op side effects compared to patients with the same
degree of CHF but without DM.
Importantly CHF patients who have not been diag-
nosed with DM should be screened for early detec- The growing two-way co-association between heart
tion of glucose intolerance or DM. failure and diabetes mellitus request that cardiolo-
gists and others caring for patients with heart failure
AREAS FOR FUTURE RESEARCH must be increasingly familiar with the management
of diabetic mellitus.
Therapies targeted to address the specific patho-
physiological alterations. In patient with CHF and References
DM are needed specific data on this population are
lacking currently. An ideal approach would be to 1. Nieminen MS Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP et
modulate myocardial substrate utilization (168) from al.Euroheart failure survey II(EHFS II) a survey on hospitalized acute heart
FFA to glucose oxidation to achieve a more efficient failure patient: Description of population. Eur Heart J 2006; 27:2725-36.
cardiac energy population.
2. Sarma S.Mentz RJ, Kwasny MJ, Fought AJ, Huffman M, Subacius H, et
Recent meta analysis has shows that additional al; on behalf of the EVEREST investigators. Association between diabetic
use of trimetazidine in CHF spatient may decrease mellitus and post-discharge outcomes in patients hospitalized with heart
failure: findings from the EVEREST trial. Eur J Heart Fail 2013; 15 :
194-202

3. Thrainsdottir IS, Aspelunt T, Thorgeirsson G, Gutnason V, Hardar-
sonT,Malmberg K et al . The association between glucose abnormalities

GCDC 2017

Cardio Diabetes Medicine 2017 233

and heart filaure in the population-based Reykjavik study diabetics Care
2005;28(3):612-16

4. King H, Aubert RE, Hermen WH. Global burten diabetes, 1995-
2025 prevalence numerical estimates, and projections. Diabetic Care
1998;21:1414-31

5. Wild S, Roglic G, Green A, Sicree R, King H, Global prevalence of diabe-
tes: estimates for the yerar 200 and projection for 2030. Diabetes Care
2004;27:1047-53

6. Bonow RO, Gheroghiate M. The diabetics epitemic a national and global
crisis Am J Met 2004;116 suppl 5A:2S-10S

7. Hall MJ, Defrances CJ, Williams SN, Golosinskiy A, Schwartzman A.
National hospital discharge survey 2007 summary. National health sta-
tistics reports No 29 Hyattsville MD. National Center for health sta-
tistics 2010. http:/www.cde gov/nchs/data/nhsr/nhsr029.pdf. Braunstein
JB, Anderson GF, Gerstenblith G,Weller W, Niefeld M.Herbert R. et.al.
Non-cardiac comorbidity increases preventable hospitalization and mor-
tality among medicare beneficiaries wtih chornic heart failure J AM coll
Cardiol 2003;42:1226-33

8. Greenberg BH,Abraham WT, Albert NM, Chiswell K, Clare R, Stough WG
et.al.b Influence of diabetes on characteristics and outcome in patients
hospitalized with heart failure a report from, the organized programme to
initiate lifesaving,. Treatment in hospitalized patients with heart failure.
(OPTIMIZE-CHF) Am Heart J 2017;154:277.el-8.

9. Nicholas GA Gullion CM Koro CE Ephross SA, Brown JB The incidence
of congestive heart failure in type 2 diabetes an update . Diabetes Care
2004-27-1879-84.

10. Kannel WB Hjordand M. Catelli WP Role of diabetes in congestive heart
failure the Framigham study Am J Cardial 1974;34;29-34

11. Boudina S. Abet ED Diabetic Cardiomyopathy refvisited Circulation
2007;115:3213-23.

Cardio Diabetes Medicine

234 Cardio Diabetes Medicine 2017

Remnant Lipo Proteins –
Residual Vascular Risk

Dr. R. Sarvanan, MD.,

Chairman, R.R.Hospital ,Thoothukudi

ABSTRACT: C-CHOLESTEROL

This article focusses on the Remnant Lipoproteins T-TRIGLYCERIDES
levels and the Residual vascular risks associated. In-
vitro animal studies and various observational studies Lipoproteins transport water insoluble Triglycerides
clearly show increased levels of Remnant Cholesterol and cholesterol between tissues and organs in the
causes atherosclerosis in the same way as increased body. They consist of a core of Hydrophobic choles-
LDL cholesterol. They also show that elevated LDL-C terol esters and triglycerides surrounded by Hydro-
are associated with atherosclerotic vascular events philic monolayer of Phospholipids, free cholesterol
but increased levels of RLP s is also correlated with and apolipoproteins .
low grade inflammation. They are measured in the
nonfasting state as Total Cholesterol minus LDL-C The different classes are Chylomicrons, Chylomicron
minus HDL-C.Even an increment of 39 mg/dl is asso- Remnants Very Low Density Lipoproteins(VLDL) In-
ciated with 2.8 fold increase in incidence of vascular termediate Density lipoproteins (IDL) LDL, Lipopro-
events. tein (a) and High Density Lipoprotein (HDL).

Randomised trials using fibrates for elevated tri-
glyceride levels slow benefits. However large ran-
domised trials with primary target of lo wering RLP s
are still missing even

though so many new Therapeutic perspectives are
in the pipeline

Definition and Introduction

Despite the success of statins in reducing athero-
sclerotic cardiovascular disease (ASCVD) there re-
mains a large residual risk for recurrent events even
in statin treated patients. Although residual risk may
be attributable to many factors like Diabetes,Obesi-
ty,Alcoholism there is considerable interest in Lipo-
protein related residual risk beyond LDL-C Reduction.
Triglycerides (TGL), a surrogate marker of TG-rich
remnant Lipoprotein have been a particular source
of interest because of consistent association with
ASCVD and the increase in TG levels in relation to
the Obesity Epidemic.

GCDC 2017

Remnant Lipo Proteins –Residual Vascular Risk 235

DEFINITIONS:2 CHYLOMICRONS:2

REMNANT LIPOPROTEIN:RESIDUAL RISK: • Formed in Jejunal enterocytes.

RLP s are products of partially Residual risk of vas- • Apo B48+phospolipid+cholesterol ester+ tri-
cular events persisting in Catabolised chylomicrons glycerides.
and patients at treatment goals according to Very
low density lipoproteins, current standards of care • Responsible for delivering exogenous & endo
or failing to meet From which a part of triglycerides lipid to liver.
are Goals including risks related to Dyslipidemia re-
moved and are strongly atherogenic. High BP,Hyper- • HDL transfers important Apo 3 to chylomicrons
glycemia and unhealthy Lifestyles. which activates lipoprotein lipase(LL).

Biochemical Pathways of Lipoproteins:2 • LL hydrolyses triglycerides → Free fatty Acids
(FFA) (source of energy)

• Progressive stripping of TG

Cardio Diabetes Medicine

236 Cardio Diabetes Medicine 2017

Advantages:
1. Inexpensive.
2. Can be done from standard lipid profile.
3. Should be in Non Fasting state.

Atherogensity of elevated RLP s:

Elevated remnant lipoprotein-cholesterol like LDL
Cholesterol enter and is trapped in the arterial wall
leading to accumulation of intimal Cholesterol and
progressive vascular injury.

Also, they are associated with lowgrade inflamma-
tory reactions like endothelial Dysfunction ,impaired
vasodilatation. Leading to thrombus formation.

CAUSES:

Obesity
Poorly controlled DM
Alcoholic excess
High estrogen Endogenous
↓
Exogenous
Drugs –Steroids oral contraceptives.
Genetic variants
↓
COMMON -------→ RARE
↓
Combination of multiple factors Chylomicronemia
Syndrome
Like Obesity | DM | High estrogen

Measurement of RLP s:1 Evidence Based:3

Limitations: MAJOR TRIALS FOR RLP ----→ ↑RESIDUAL
RISK:
• Remnant Lipoproteins are different both in compo-
sition of lipids and apolipoproteins as a result of RLPs contribute to atherogenesis was first made by
different stages of lipolysis at the time of study . Zilversmit in 1979.

• -Formed by two different pathways . • Framingham Off spring study Serum levels of RLP
correlate well with the risk of events in women with
• -So very difficult to measure them precisely. established CAD.

Alternatively : • Honolulu heart study :Serum levels of RLP correlat-
ed well with CV events of asian men.
Non Fasting Remnant Lipoprotein Cholesterol=Total
Cholesterol –HDL-c –LDL-cholesterol. • ACCORD trial –RLP level correlated well with the
CV risks in diabetic women in post prandial sub-
study.

GCDC 2017

Remnant Lipo Proteins –Residual Vascular Risk 237

• Remnant lipoproteins levels correlated well with (ANGPTL3 ANGPTL4) and IHD.
CV risk also
• Pivotal role of Peroxisome –Proliferator Activated
• in Japanese patients with established CAD Receptor PPAR is controlling key areas lipid me-
tabolism leading to the drug Pemafibrate which is
• In patients with Fredrickson type III dysbetalipo- now being evaluated in PROMINENT CARDIOVAS-
protienemia (Familiar type due to defective apo E) CULAR outcomes study.
serum remnants are increased leading to develop-
ment of xanthomas and risks for cv events . • CANTOS ( Canakinumab-Antiinflammatory Throm-
bosis outcomes study).
• Recently , levels of RLPs defined as (sum of VLD3
+ IDL) are highly associated with risk for CV events • -Atherosclerosis multidimensional event.
in Framingham heart study and Jackson heart
study and meta analysis performed in both co- • Canakinumab is a monoclonal antibody selectively
horts. neutralited IL-1. which plays multiple roles in athero
thrombolic process.
• Thus, RLPs similarly correlated with CV events in
both Caucasians and African Americans. CONCLUSION:

• The Residual Risk reduction initiative has highlight- Perhaps, therefore we need to revise how we man-
ed the importance of this RLPs related dyslipid- age residual vascular risk since Atherosclerosis is
emia as a major risk factor especially in patients multifactorail.not only we need to consider cholester-
with Diabetes Melitus Obesity. ol related residual risk typified by high LDL-C levels
but also by high levels of triglyceride rich RLP s or
Therapeutic Perspectives:4 increased inflammation.

• Therapeutic targeting of Triglyceride levels below Given the escalating burden of cardiomatabolic dis-
150 mg is recommended in patients at high risk eases globally, this would make sense clinically and
of Vascular Diseases after LDL lowering. fiscaly.

Life Style Pharmocological REFERENCES:

1. Weight reduction 1. Statins 1. Pharmacology &Therapeutics. 141.2014.358-367. AneHe varbo.marianne
Benn, BorgeG, Nordestgaard., Associate Editor : M.J.Chapman.
2. Regular Physical 2. Niacin
activity 2. Remnant Lipoprotiens and Atherosclerotic disease Feb10.2014., Peter.p.
Toth.M.D.Ph.D.FACC American college of Cardiology.
3. Smoking cessation 3. Fibrates
3. Current opinion in Lipidology Remnant Lipoproteins. Vaebo, AneHe,Nord-
4. Reduced alcohol 4. Considering data from estgaard,BorgeG, August.2017-volume 28-Issue 4-P300-307.
largely completed and
↓ ongoing trials. 4. R31 Editorial .28 July.2017. Targeting residual Cardiovascular risk: Lipids
Act decreasing Hepatic and beyond. Prof .Jean Charles Fvuchart. Prof. Michael Hermans. Prof.
Secretion and Final word is not said Pierre Amarenco.
↑ Hepatic Clarence of for the effective of
VLDL these drugs in lowering
Residual risk.

• Omega -3 Fatty acids- Fish oils here conflicting
results.

• Drugs targeting apo B –mipomersen MTP inhibi-
tor-Lomitapide.

• Antibodies against Plasma Proprotein Convertase
Subtilisiol Kexin type a (PCSKQ).

• Promotes update of LDL and increases desvada-
tion of LDL.

• Genetherapy for LDL deficiency.

• Genetic studies showing evidence of associa-
tion between apo c III|Angiopoietinslike 3 and 4

Cardio Diabetes Medicine

238 Cardio Diabetes Medicine 2017

Treatment of Acute Ischemic Stroke

Dr B.Kannan, DM. (Neuro)

Consultant Neurologist, Sundaram Arulrhaj Hospital,Tuticorin.
Senior Asst. Professor ,Govt Thoothukudi Medical College , Tuticorin.

ABSTRACT heart failure and venous thromboembolism) in a
stroke unit staffed by specially trained personnel.
Timely successful reperfusion is the most effective The management of acute ischemic stroke starts
treatment for patients with acute ischemic stroke. with the prompt recognition of the diagnosis in
Systems of care should be optimized to maximize the field and attention is currently aimed at opti-
the number of patients with acute ischemic stroke mizing the time to reperfusion. In the emergency
able to receive reperfusion therapy. department and the angiographic suite

INTRODUCTION PRINCIPLES OF ACUTE STROKE CARE

Stroke is defined as abrupt onset of neurological defi- The three main principles of acute stroke care
cit that is attributable to a focal vascular cause(may- are (1) Achieve timely recanalization of the occlud-
be ischemia or haemorrhagic ). According to WHO, ed artery and reperfusion of the ischemic tissue
Stroke is the second leading cause of death in the (2) Optimize collateral flow (3) Avoid secondary
world after ischemic heart diseases. Whereas it is the brain injury
third leading cause of death in India after Ischemic
heart diseases and COPD .The estimated adjusted (1) Recanalization and reperfusion are the main-
prevalence rate of stroke range, 84-262/100,000 in stay of acute stroke treatment and can reduce stroke
rural and 334-424/100,000 in urban areas(according treatment and can reduce infarct size and reverse
to 2013 data). The incidence rate is 119-145/100,000 neurologic deficits. Recanalization is defined by the
based on the recent population based studies degree of reopening of the occluded artery. Reper-
fusion is measured by the degree of flow reaching
Over the past 2 decades, the therapeutic approach to the previously hypoperfused brain region. Opening
acute ischemic stroke has been deeply transformed. the occluded artery works because, in most cases,
Long gone is the nihilism of former times, now when the occlusion occurs, an area of brain tissue
replaced by the excitement of proven treatment becomes hypoperfused but is initially not infarcted.
options that can reverse ischemia and brings back This tissue represents the ischemic penumbra that
function to patients who were otherwise destined can be salvaged if adequate blood flow is promptly
to death or severe disability .The wide adoption of reestablished. Advanced brain imaging with CT
IV thrombolysis that began 20 years ago has re- perfusion or magnetic resonance (MR) diffusion/
cently been followed with clear evidence that the perfusion can visualize this tissue at risk (penum-
addition of endovascular treatment with mechan- bra imaging). Chemical thrombolysis with recombi-
ical thrombectomy can further improve outcomes nant tissue plasminogen activator (rtPA), also known
in patients with severe neurologic deficits from a as alteplase and mechanical embolectomy with a
proximal intracranial vessel occlusion. retrievable stent are the two evidence – based strat-
egies to achieve reperfusion.
The treatment of acute stroke also includes
adequate hemodynamic management, monitoring (2) Collateral flow is responsible for keeping the
and management of ischemic brain edema and ischemic penumbra viable. It provides enough flow
early recognition of and therapy for systemic com- to prevent critical ischemia and infarction but not
plications (such as infections, cardiac arrhythmias,

GCDC 2017

Treatment of Acute Ischemic Stroke 239

sufficient flow to maintain normal cellular function. ysis with rtPA and endovascular thrombectomy with
This explains why the acute neurologic deficits ex- a retrievable stent improve neurologic outcomes in
ceed what would be expected for the established patients with acute ischemic stroke. Both treatments
infarct core at the time of presentation and why neu- should be administered as quickly as possible after
rologic function can improve after reperfusion. This stroke onset can be combined and are safe in ap-
collateral flow, however is often tenuous and can propriately selected candidates. IV thrombolysis and
sustain viability only for a limited period of time. mechanical thrombectomy can produce reperfusion
Thus without recanalization the ischemic penum- injury after recanalization. Reperfusion injury can
bra is destined to progress to infarction. Collateral manifest with hemorrhage and edema. It is more
flow can be protected by avoiding blood pressure severe when the area of established infarction is
drops and supported by the administration of IV larger. Good patient selection (ie, absence of large
fluids. The value of keeping the head of the bed ischemic core ) and prompt treatment are crucial to
flat for patients with acute ischemic stroke is avoid this complication.
being investigated in the ongoing head position
in stroke trial (Headpost) and should be weighed Intravenous Thrombolysis
against the risk of aspiration. Hemodynamic aug-
mentation with vasopressors may be beneficial in IV Thrombolysis with rtPA is proven to be effective
well selected cases (such as patients with cervical in improving functional outcomes after an ischemic
internal carotid artery occlusion without tandem stroke up to 4.5 hours after symptom onset. The US
intracranial occlusion) but the safety and efficacy food and drug administration (FDA) has only ap-
of this strategy is otherwise unknown. Invasive proved rtPA for use within 3 hours of stroke onset
interventions to improve collateral flow remain ,but regulatory agencies in most other countries (in-
investigational. cluding those in the European union) have approved
its administration within 4.5 hours of stroke onset.
(3) Despite promising results in basic and transla-
tional experiments numerous neuroprotective agents The initial evaluation of a patient with a possible
have failed to improve outcomes in clinical trials acute stroke in emergency department should focus
. Hypoglycemia can exacerbate energy failure and on establishing whether the patient is eligible for
should be strictiy averted. Hypoglycemia might reperfusion therapy .Necessary information includes
also be deleterious so far , we know that it cor- the time the patient was last known to be well, med-
relates with worse outcomes after an ischemic ical conditions or recent surgery that could con-
stroke but do not have proof that its corrections traindicate thrombolysis, neurologic examination
improves out comes. to calculate the National institutes of health stroke
scale (NIHSS) score, a capillary glucose level, blood
The stroke Hyperglycemia insulin Network Effort pressure and brain imaging (CT scan with a
(SHINE) trial is a randomized controlled trial com- CT angiogram depending on whether endovascular
paring tight glycemic control with IV insulin to therapy is being considered).
maintain a glucose level between 80 mg/dl and
130 mg/dl versus strandard glycemic control using Indications
subcutaneous insulin dosed according to a sliding
scale to keep the glucose level lower than 180 • Clinical diagnosis of stroke
mg/dl in patients with acute ischemic stroke
within 12 hours of symptom onset It is hoped • Onset of symptoms to time of drug
that this trial will answer the question whether
tight glycemic control is safe and beneficial after • administration ≤4.5hrs
an acute ischemic stroke . Fever is associated with
worse clinical results; thus treating fever may be • CT scan showing no hemorrhage or
beneficial. The value of hypothermia continues
to be investigated preventing infections (which nota- • edema of >1/3 of the MCA territory
bly includes dysphagia assessment before any oral
intake) and early recurrent strokes are additional • Age ≥ 18 years
priorities in the care of the patient with acute stroke.
• Consent by patient or surrogate
ACUTE REPERFUSION TREATMENTS:
Contraindications
There is incontrovertible evidence that IV thrombol-

Cardio Diabetes Medicine

240 Cardio Diabetes Medicine 2017

• Sustained BP >185/110 mmHg despite treatment 90 days, although it was associated with a lower
risk of symptomatic intracerebral hemorrhage (which
• Platelets <1,00,000 ; HCT <25 % ; Glucose<50 was low in both treatment groups).
or >400 mg/dl
No other thrombolytic agent has been approved
• Use of heparin within 48hours and prolonged for use in ischemic stroke . In emergency de-
PPT, or elevated INR partments of medical centers with more limit-
ed capabilities, patients can receive the bolus
• Rapidly improving symptoms of rtPA and then be transferred to a primary
stroke centre while the rest of the dose of the
• Prior stroke or head injury within 3 months ; prior drug is being infused (the drip- and –ship strategy).
intracranial hemorrhage Hemorrhage is the most dangerous complication af-
ter thrombolysis.
• Major surgery in preceding 14 days
ACUTE ISCHEMIC STROKE
• Minor stroke symptoms
The reported rates of symptomatic intracerebral
• Gastrointestinal bleeding in preceding 21 days hemorrhage (sICH) have varied (between 1.9% and
6.4%), depending on its definition and the design
• Recent myocardial infarction of the study . However, most cases of SICH are
caused by reperfusion injury and worsen strokes
• Coma or stupor that were already severe and destined to be disabling.
Hemorrhagic transformation of a large infarction can
Recenty, the indications and contra indications for increase the risk of death, but sICH rarely negates
IV rtPA have been revisited in a scientific state- what would have otherwise been a good recovery.
ment of the American Heart Association(AHA) and The risk of SICH is increased with old age , diabetes
modified by the FDA in the package insert for the mellitus, severe hyperglycemia uncontrolled hyper-
drug. As a result, more patients can be considered for tension and large hypodensity on baseline CT scan.
IV thrombolysis in clinical practice. IV thrombolysis The risk of sICH might also be higher in patients with
should not be withheld because of advanced age, cerebral microbleeds, although this association is not
and mild but disabling deficits justify treatment. In- entirely certain. When sudden neurologic decline oc-
dividualized clinical judgment is necessary when curs during rtPA infusion , the infusion should be im-
deciding whether to recommend thrombolysis mediately stopped and a CT san should be obtained
to patients with weaker indications (such as non emergently, whenever postthrombolysis sICH is di-
disabling deficits)or relative contraindications. The agnosed, treatment consists of control of hyperten-
safety and efficacy of IV thrombolysis in pediatric sion (systolic target 140 mm Hg to 160mm Hg ) and
patients (younger than 18 years of age) is not well reversal of the fibrinolytic effect with cryoprecipitate
established. (10units) or an antifibrinolytic agent (Tranexemic acid
10mg/Kg to 15 mg/Kg IV over 20 minutes or Amino
IV rtPA infused within 3 hours of symptom onset in- caproic acid 5Grams IV followed by an infusion of
creases the chances of functional independence at 1Gram/hour if needed).Additional cryoprecipitate may
3 month by one- third. The benefit is time dependent be given if the serum fibrinogen level remains below
and much stronger when the drug is administered 150mg/dl. Orolingual angioedema is a rare but po-
within the first 90 minutes after symptom onset. Old- tentially serious complication of rtPA administration.
er patients and those with a very severe stroke The risk is higher in patients previously taking an-
at presentation have worse prognosis but can still giotensin converting enzyme inhibitors. It is typically
benefit from IV rtPA. The benefit is less robust for asymmetric and tends to involve the hemiparetic side
patients treated between 3 and 4.5hours , but rtPA the most severe cases can compromise airway pa-
is still beneficicial in this extended window . tency thus careful monitoring is indispensable. Treat-
ment consists of a combination of diphenhydramine
The standard dose of IV rtPA for acute ischemic (50mg IV),ranitidine (50 mg IV),and dexametha-
stroke is 0.9mg/kg with 10% administered as a bolus sone(10 mg IV).
and the remainder infused over 1 hour. The total
dose should not exceed 90mg.The phase 3 Enhanced While IV thrombolysis is the standard of care for eligi-
control of Hypertension and thrombolysis stroke ble patients with acute ischemic stroke,this treatment
study (ENCHANTED) enrolled 3310 predominantly has limitations. In addition to its short time window
Asian patients to receive either 0.9mg/kg or 0.6mg/
kg of IV rtPA within 4.5 hours of stroke onset. The
reduced dose was inferior to the standard dose for
the end point of death or any degree of disability at

GCDC 2017

Treatment of Acute Ischemic Stroke 241

and contraindication in patients with increased bleed- spective studies and subsequently confirmed in a
ing risk,IV rtPA often fails recanalize proximal artery sub analysis of the multicenter randomized clinical
occlusions caused by large clots. These are most dis- trial of endovascular treatment for acute ischemic
abling strokes and strong evidence now exists that stroke in the Netherlands (MR CLEAN) trial. it is be-
these patients should be considered for endovascu- coming increasingly clear that most interventions
lar therapy. can be safely completed using conscious sedation
An appropriately powered large randomized trial will
Mechanical Thrombectomy be necessary to conclusively determine if conscious
sedation should be preferred over general anesthesia
Although endovascular recanalization treatment for during endovascular stroke therapy.
selected patients with severe acute ischemic stroke
has been practiced in many centers for decades, Perhaps the main question is whether the outcomes
the publication of several recent positive trials has observed in the randomized trials can be replicated
showed this therapy to the status of evidence- based in daily practice. To achieve this goal, triaging mech-
treatment for patients with large intracranial artery anisms must be refined and expertise must become
occlusion. more readily available. Organization and implemen-
tation of stroke networks around comprehensive
Candidates for acute Endovascular stroke stroke centres with 24/7 neurointerventional centers
Therapy will have to prove compliance with strict metrics of
efficiency and safety.
• Age 18 years
SPECIAL SITUATIONS
• NIHSS Score 6
Special clinical situations remain for which the ev-
• Time from symptom on set to groin puncture idence is insufficient to determine the best course
6 hours of action until more definite data become available,
these cases should be approached considering in-
• Good prestrike functional status dividual factors and what is known from collective
experience.
• Aspects score 6 on baseline CT scan
Wake –up Stroke
• Presence of proximal intracranial artery occlu-
sion Patients whose neurologic deficits are first noticed
upon their awakening represent a particular chal-
Exclusion criteria : ASPECTS score <6 in baseline CT lenge to the clinician the same applies to those
scan However, the non-contrast CT scan is not with unclear time of onset (such as when the pa-
sensitive for the visualization of early ischemia. tient is aphasic and the onset of symptoms was not
One of the trials used multiphase CT angiography to witnessed).These situations constitute formal con-
evaluate collateral vessels, and another required a traindications for IV rtPA,but it is widely agreed that
CT perfusion showing a limited infarct core and some of these patients may benefit from reperfusion
evidence of penumbra before randomization. Fur- therapy. When the baseline CT scan shows no evi-
thermore, many patients in trials that did not require dence of large established infarction it is likely that
CT perfusion by protocol had this imaging before advanced imaging with CTperfusion or MR diffusion
inclusion in the study because that was the prevail- /perfusion may identify those patients who can be
ing practice in the enrolling centre ,CT perfusion can safely treated and can improve after successful re-
provide more reliable assessment of the ischemic re- canalization observational studies support this ap-
gion, but its acquisition requires additional time M RI proach , Which is currently being tested in the DWI or
diffusion/perfusion is broadly considered the most CTP Assessment with clinical mismatch in the triage
accurate method to determine the ischemic core and of wake up and late presenting strokes undergoing
the extent of the penumbra but this technique is less neurointervention (DAWN),perfusion imaging selec-
available New software packages promise to accel- tion of ischemic Stroke patients for Endovascular
erate the time required to obtain perfusion imaging therapy (POSITIVE), Diffusion and perfusion imaging
yet at this time, it is unclear if the additional time evaluation for understanding stroke evolution 3 (DE-
needed to obtain these images is justified . FUSE 3), and A phase lla safety study of intravenous
Thrombolysis with Alteplase in MRI- selected patients
A growing body of evidence suggests that interven- (MR WITNESS) trials.
tions performed under conscious sedation have bet-
ter out comes than those performed under general
anesthesia. This finding was first reported in retro-

Cardio Diabetes Medicine

242 Cardio Diabetes Medicine 2017

Intravenous Thrombolysis in patients Taking newer Even among patients who are treated with reperfu-
anticoagulants Iv rtPA can be administered within sion strategies, mortality remains high(30% to 35%)
3 hours of symptom onset to patients taking warfa- therefore many cinsider extending the therapeutic
rin whose international normalized ratio (INR) is 1.7 window for IV thrombolysis beyond 4.5 hours and
or less However, no adequate safety data with the for mechanical thrombectomy far beyond 6 hours
newer anticoagulants (The direct thrombin inhibitor in patients with basilar artery occlusion who do not
dabigatran and the factor Xa inhibitors rivaroxaban have a large established pontine or cerebellar infarc-
apixaban, and edoxaban) exist. Readily available lab- tion to be reasonable.
oratory studies cannot quantify the degree of anti-
coagulation. Thus, it is most prudent to withhold Future Directions
thrombolysis in patients taking these agents. Howev-
er patients with proximal intracranial artery occlusion Current efforts are focused on increasing the effi-
may benefit from mechanical thrombectomy. ciency of systems of care and investigating new
strategies for acute stroke therapy the common
Minor and rapidly improving deficits objective is to increase the number of patients with
acute ischemic stroke who can regain perfusion of
Although thrombolysis is often with held because the the ischemic tissue before infarction is established.
symptoms are considered mild or patients appear to
be rapidly improving, Several observational studies Mobile stroke units are rapidly gaining acceptance.
have shown that up to one-third of patients who are These are special ambulances equipped with a por-
otherwise eligible for thrombolysis but do not receive table CT scanner and digital technology to enable
it for these reasons are disabled at 3 months. Thus, telecommunication with a stroke specialist they have
one must be very careful when assessing these pa- been shown to allow safe initiation of IV thrombol-
tients IV rtPA might be justified when the NHSS score ysis while en route to the stroke centre. This option,
is low but the symptoms are nonetheless disabling although expensive can be very welcome solution
for the patient(eg, hemianopia) for some heavily populated urban communities.
Dispatchers and paramedics must receive specific
Improving deficits that are still disabling at the time stroke education to optimize the efficiency and safe-
of the neurologic evaluation may similarly warrant ty of these mobile units.
thrombolysis The value of IV rtPA within 3 hours of
symptom onset in patients with mild (NIHSS score Ways to extend the therapeutic window (beyond
of 5 or less) or rapidly improving deficits is being in- 4.5 hours for IV therapy and 6 hours for mechanical
vestigated in the phase IIIB, Double-blind, Multicenter thrombectomy ) are being actively investigated us-
study to Evalute the Efficacy and safety of Alteplase ing more fibrin- specific fibrinolytic agents has been
in patients with mild stroke rapidly improving symp- considered a promising option for years trials using
toms and Neurologic Deficits(PRISMS) trial. desmoteplase showed no benefit, but tenecteplase
is still beging studied. Radiologic identification of
Posterior circulation strokes patients with better collateral flow resulting in per-
sistently salvageable tissue is broadly considered a
Randomized trials of IV thrombolysis and mechanical reasonable albeit still unproven approach. Selection
thrombectomy (except for very few patients enrolled of candidates using perfusion imaging modalities is
in the contribution of intra- arterial thrombectomy in being tested in ongoing trials (DAWN,DEFUSE3,and
acute ischemic stroke in patients with intravenous MR WITHNESS).
thrombolysis [THRACE] trial) have been restricted to
patients with anterior circulation strokes. yet clinical Collateral flow augmentation is an other proposed
experience with treating posterior circulation infarc- strategy in current practice, this is sometimes at-
tions with these therapies exists. Basilar artery oc- tempted with vasopressors evidence is restricted to
clusions can be devastating unless recanalization small case series and one pilot feasibility study yet
it achieved registry data indicate that IV rtPA and hemodynamic augmentation with vasopressors can
mechanical thrombectomy can result in functional occasionally work, in particular in patients with prox-
independence at 3 monthsin30% to 40% of cases; imal vessel occlusions who are not deemed candi-
these rates of favorable outcome are clearly great- dates for endovascular recanalization or in whom the
er than those reported without reperfusion therapy. recanalization attempt was unsuccessful mechanical
The value of endovascular therapy for acute basilar techniques for collateral recruitment(such as exter-
occlusion is currently being investigated in the bas- nal counterpulsation and intraaortic inflation devices)
ilar artery international cooperation study (BASICS). have been shown feasible and but their efficacy re-

GCDC 2017

Treatment of Acute Ischemic Stroke 243

mains to be proven.

The evolution of emergency treatment for acute
ST-segment elevation myocardial infarction can in-
form the future of acute stroke therapy from a prox-
imal artery occlusion Fibrinolysis followed by endo-
vascular therapy was initially a common practice but
was later abandoned after randomized trials demon-
strated that proceeding directly to the endovascular
intervention was a superior strategy. Once systems
of care are optimized to guarantee fast access to the
angiographic suite for patients with acute stroke it
will be necessary to perform a trial comparing IV
thrombolysis followed by mechanical thrombectomy
for patients with server stroke and proven proximal
artery occlusion.

Conclusion

Acute ischemic stroke is a medical emergency in
which every minute counts. Achievement of reper-
fusion can reverse neurologic deficits even if severe,
and allow patients to regain function. Two reperfusion
strategies are now proven IV rtPA and mechanical
thrombectomy. They are both safe and effective for
the right candidates. Patient selection is crucial to
optimize outcomes but the attitude of the clinician
should be that treatment should be given unless a
solid contra indication exists.

At this juncture efforts should be concentrated on re-
fining systems of care to allow more patients to have
access to reperfusion treatment expanding the num-
ber of candidates for intervention will require contin-
uous education of the community to recognize signs
of stroke, improving the initial triage of patients with
stroke and speeding evaluation and treatment in the
hospital. Ongoing trials are also evaluating the pos-
sibility of extending the therapeutic window by using
advanced imaging modalities to identify patients in
whom good collaterals have preserved tissue viability
for a longer time. Collateral augmentation strategies
and ultra- early administration of neuroprotective
agents may provide additional treatment venues in
the future.

Cardio Diabetes Medicine

244 Cardio Diabetes Medicine 2017

Hypoglycemic Heart-
Cardiologist Perspective

Dr. Senthilkumar Nallusamy,
Dr. M. Shyamala Priya & Dr. A. Balaji

*Chief Cardiologist, Apollo Hospital, Trichy And Rana Hospital,
Trichy **&***Resident, Apollo Hospital, Trichy.

INTRODUCTION: epinephrine &norepinephrine may induce vasocon-
striction and peptides such as endothelin have pro-
The risk of hypoglycemia associated with intensive nounced effects on intravascular coagulability and
glucose control in acutely ill patients remains an viscosity.
important concern with an incidence of severe hy-
poglycemia as high as 19% observed in the report- -- Increased viscosity because of increase in eryth-
ed randomized trials. This concern maybe especially rocyte concentration coagulation is promoted by
important in the treatment of ACS,in which counter platelet activation increases P-selectin expres-
hormone response associated with hypoglycemia sion(marker of platelet activation),factor 8 lev-
may prove to be particularly deleterious to ischemic els,von-willebrand factor
and infarcting myocardium.
-- Influence platelet aggregability and alter several
This article “HYPOGLYCEMIC HEART” will review the components of the inflammatory cascade
basic cardiac pathophysiological changes during hy-
poglycemia,the clinical cardiac events occurring due -- Reduction in plasminogen activator inhibitor-1 in
to hypoglycemia and diabetic therapeutic modifica- patients with Type 1 DM
tions required to prevent adverse cardiac outcomes.
-- Endothelial functions may be compromised be-
ADA’s DEFINITION OF HYPOGLYCEMIA: cause of increase in CRP, mobilization and activa-
tion of neutrophils & platelets
-Symptoms consistent with hypoglycemia
-- Reduced systemic fibrinolytic balance and en-
-Low plasma glucose concentration measured with hanced platelet monocyte aggregation provide a
precise method (not a glucose monitor) biological rationale for the increased rates of acute
ischemic events seen in patients with DM& hypo-
-Relief of symptoms after the plasma glucose level glycemia
is raised
-- Subjects with Type-II DM demonstrate greater
CARDIOVASCULAR CONSEQUENCES OF platelet aggregation despite treatment with aspirin
SEVERE HYPOGLYCEMIA: and adenosine diphosphate receptor antagonists
than their counterparts without DM
Hypoglycemia Causes:-
INFLAMMATORY ABNORMALITIES:
• Blood coagulation abnormalities
-Increase in circulating inflammatory markers such
• Inflammation as CD40,CD40 ligand,interleukin-6,high sensitivity
CRP,oxidative stress and other proinflammatory and
• Endothelial dysfunction atherothrombotic biomarkers such as VCAM-1,ICAM1,
E-SELECTIN,VEGF along with TNF-α
• Sympathetic nervous system activation
ENDOTHELIAL DYSFUNCTION:
BLOOD COAGULATION ABNORMALITIES:
-Abnormal endothelial function remains as early
Increase in counterregulatory hormones such as

GCDC 2017

Hypoglycemic Heart- Cardiologist Perspective 245

marker of subclinical atherosclerosis and that sub- 4. Changes in heart rate variability
jects with T2DM demonstrate altered endothelial de-
pendent and independent responses 5. ST-T changes

-With type 1 DM hypoglycemia resulted in a reduction 6. Atrial fibrillation
in arterial wall stiffness and augumentation index
,probably as a result of insulin induced changes in 7. The ECG changes are primarily due to catechol-
the arterial endothelium amines and hypokalemia which is the probable
mechanism for “Dead in bed syndrome”.
Hypoglycemia induced endothelial dysfunction may
act in concert with inflammatory biomarkers and MYOCARDIAL EFFECTS DUE TO
blood coagulation abnormalities to promote cardio- HYPOGLYCEMIA:
vascular events.
Myocardial effects are mediated by insulin and epi-
SYMPATHOADRENAL RESPONSES: nephrine

-- Sympathetic response to hypoglycemia represents The following are the myocardial effects of hypogly-
a counterregulatory mechanism to diminish the cemia:-
impact of abnormally low glucose levels
• Ejection fraction is increased
-- Release of catecholamines has profound effects
on the cardiovascular system ,directly altering car- • Peak filling rate is increased
diac contractility,myocardial work,cardiac output
and therefore oxygen demand • EDV is increased

-- This may induce ischemia in subjects with preex- • Prolonged severe hypoglycemia results in depres-
isting coronary artery disease1 sion of myocardial function and causes LV dys-
function.
-- Catecholamine excess also has direct effects on
platelet reactivity and may potentially be proarryth- HEMODYNAMIC CHANGES DUE TO
mic HYPOGLYCEMIA

-- Hypoglycemia has been shown to significantly Hemodynamic changes are primarily due to epineph-
prolong QT interval, which was an independent rine
predictor of mortality
• Systolic BP is increased
-- There is also a significant relationship between as-
ymptomatic hypoglycemic episode and ventricular • Diastolic BP is decreased
extrasystoles/nonsustained VT
• Pulse pressure is increased
-- Furthermore antecedent hypoglycemia may impair
autonomic function ,leading to reduced heart rate • Increase in central aortic pressure
variability which is an independent predictor of
poor outcomes in population with DM • Heart rate is increased

-- Catecholamine excess may also induce hypoka- TRIALS HIGHLIGHTING ABOUT
lemia and increased intracellular ca2+,this can HYPOGLYCEMIA AND CV EVENTS:-
result in delayed afterdepolarisation ,along with
prolongation of actionpotentials by blockade of ACCORD TRIAL2:-
current through the human ether-a-go-go related
gene[hERG] potassium channel,all of which have • 10,250 patients
been implicated in the development of lethal car-
diac arrhythmias • Mean age 62, Duration of DM > 10years.

ECG CHANGES IN HYPOGLYCEMIA: • Baseline HbA1C 8-1

1. Prolongation of QT interval • Goal <6

2. Tachycardia • Hypoglycemia, mortality, higher in intensive group:

3. Ventricular ectopic beats • Rapid decrease in HbA1C (within 6months)
ADVANCE TRIALS3:-

• 11,140 patients

• Mean age 66 years

Cardio Diabetes Medicine

246 Cardio Diabetes Medicine 2017

• Duration of DM – 8 years and drug administration criteria of safety with re-
spect to a composite cardio vascular outcome with
• Baseline HbA1C 7-2 no excess in rates of heart failure hospitalisation.
• Goal < 6-5
• The EMPA-REG outcomes study reported safety
• High risk for CVD and superiority of the SGLT-2 inhibitor EMPAGLI-
FLOZIN in individuals with type 2 DM and cardio-
• Hypoglycemia more in intensive arm, no reduction vascular disease accompanied by marked reduc-
in macrovascular disease tion in cardiovascular and all-cause mortality.

• Gradual reduction in HbA1C (2years) • The US food and drug administration has approved
VADT TRIAL4:- a new indication for LIRAGLUTIDE for reducing risk
of MI, Stroke and cardiovascular death in adults
• 1791 patients with type 2 DM who have established cardiovas-
cular disease.
• Mean age 60 years
TAKE HOME MESSAGES -
• Duration of DM- 11.5 years CARDIOLOGIST’S PERSPECTIVE:

• Base line HbA1C 9.4 -- More worried about hypoglycemia than hypergly-
• Goal <6 cemia because it tilts the balance of a chronic as
well as acute cardiac patients suddenly.
• 40% had precious CV events
-- Recognize that episode of severe hypoglycemia
• Hypoglycemia more, no difference in macro or mi- are associated with increased all cause and cardio-
cro vascular outcomes vascular mortality in patients with T2DM.Various
proinflammatory, prothrombotic, proatheroscle-
• Medium decrease in HbA1c rotic and proarrythmogenic processes have been
suggested as potential mediators for the adverse
UKPDS5:- effects of hypoglycemia on the heart

-- 5102 patients -- To reduce macrovascular events or should aim at
gradual sugar lowering without precipitating hypo-
-- Mean age 54 glycemia

-- Newly diagnosed DM -- With the paucity of data in the ACS setting, a more
conservative approach to glucose management
-- Achieved HbA1c – 7 should be used for patients with ACS events. The
recommended glucose targets of below 180mg/dl
-- More hypoglycemia in patients with sulfonylurea are reasonable based on the existing data6.
and insulin
-- Recognize that hypoglycemia is exceedingly com-
-- No change in events at 7 years mon, and that this is usually attributable to sul-
fonylurea and insulin therapy. Renal dysfunction
-- Follow up further period of 9 years showed gradual and older age are also important risk factors for
reduction in HbA1C with reduction in macrovascular hypoglycemia
events.
-- Metformin and DPP4 inhibitors produce less hypo-
DRUGS – HYPOGLYCEMIA AND CV EVENTS glycemia and likely to be cardioprotective.

• Newer glucose lowering agents such as the incre- -- Welcome the drugs which produce less or no hy-
tins(GLP receptor agonists and DPP-4 inhibitors) poglycemia which are safe for the heart and at the
and SGLT2 inhibitor classes of agents are associat- same time control macro and microvascular events
ed with much lower rates of hypoglycemia relative significantly.
to sulfonylureas or insulin, and maybe considered
as preferred add on therapies to metformin in pa- CONCLUSION:
tients with DM
Severe hypoglycemia represents a common and
• During the review process, the primary results of challenging issue in the optimal management of car-
3 cardiovascular outcome trials in DM were pub-
lished. The TECOS and ELIXA studies demonstrat-
ed that the DPP-4 inhibitor SITAGLIPTIN and the
GLP-1 receptor agonist LIXISENATIDE respectively
were non inferior to placebo and met the US food

GCDC 2017

Hypoglycemic Heart- Cardiologist Perspective 247

diovascular diseases accompanied with DM.There is
an association between severe hypoglycemia and
adverse outcomes,but the pathophysiology and di-
rect causal relationships linking DM with cardiovas-
cular disease, pharmacological therapy and adverse
outcomes remain to be elucidated.Novel therapies
have demonstrated that the newer drugs having low
rates of hypoglycemic effect and also having bet-
ter outcome in cardiovasculardisease.The next 5 to
6 years will have wealthy trials that will guide the
more specialized treatment modalities for this high
risk sub group.

REFERENCES:-

1. Kim A. Connelly, Andrew T.Yan, Lawrence A. Leiter et al: cardiovas-
cular implications of hypoglycemia in diabetes mellitus. Circulation.
2015;132:2345-2350.

2. Accord Study Group Gerstein HC, Miller ME et al: Long term effects of
intensive glucose lowering on cardiovascular outcomes. N Engl J Med
364: 818,2011.

3. Patel A ,Macmahon S, Chalmers J etal: Intensive blood glucose control
and vascular outcomes in patients with Type – 2 diabetes. N Engl J
Med 358: 2560.2008.

4. Duckworth W, Abraira C, Moritz J, et al: Glucose control and vas-
cular complications in veterans with type-2 diabetes. N engl J
Med360:129.2009.

5. Holman RR, Paul SK, Bethel MAetal: 10year follow up of intensive glucose
control in type-2 diabetes. N Engl J Med 359:1577,2008.

6. Gara PT, Kushner FG, Ascheim DD, etal:2013 ACCF/AHA guideline for
the management of ST elevation myocardial infarction : A report of the
American College of Cardiology Foundation / American Heart Association
Task force on practice guidelines. Circulation 127:e362,2013.

Cardio Diabetes Medicine

248 Cardio Diabetes Medicine 2017

Listening to Our Gut:
Microbiomes and NCD /CVD

Dr. Rajesh Upadhyay,

Director & Head, Department of Gastroenterology & Hepatology
Max Superspeciality Hospital, Shalimar Bagh, Delhi

Human microbiota contains 10-100 trillion microbial and Lactobacillus is seen in children with Type I dia-
cells (37 trillion total cells in human body) with >1000 betes mellitus. Such children also have lower counts
species.Bacteroidetes and Firmicutes are dominant of butyrate producing bacteria. A clear relationship
(>90% of the total microbial population) in human in- has been demonstrated between T2D and composi-
testine. Each individual has a unique set of intestinal tional changes in the gut microbiota. There is a low-
microbiota, the formation of which starts at the time er relative abundance of Firmicutes, Bifidobacterium
of birth and is dependent on a number of factors and Faecalibacterium (anti-inflammatory) and a high-
such as – genetic, environmental and immunological er proportion of Bacteroidetes and Proteobacteria in
status. Diet has an important role in the composition diabetics. Diabetics also have a significantly lower
of these bacteria. The microflora subserves import- number of butyrate producing bacteria.Changes of
ant functions in human body such as protective from gut microbiota composition are strongly associated
pathogens, trophic functions e.g. control of epithelial with increased adiposity, β-cell dysfunction, metabol-
cell proliferation /differentiation/ development and ic endotoxemia, systemic inflammation, and oxida-
homeostasis of the immune system and metabolic tive stress associated with T2DM.Improvement of gut
functions e.g. fermentation of non-digestible dietary microbiota leads to stimulation of insulin signalling,
residue and endogenous mucus, salvage of energy B cell preservation, regulation of insulin secretion, fat
(as short-chain fatty acids) and absorbable nutri- accumulation, cholesterol levels and has anti-inflam-
ents. The mechanisms include production of antimi- matory effect.
crobials, destruction of toxin receptors, competitive
exclusion of pathogens, organic acid production, Bifidobacterium and Lactobacillus strains have been
enhanced intestinal barrier function, enhanced IgA most widely used in animal and clinical studies with
secretion and immune regulation. diabetes.A number of studies have shown that probi-
otic supplementation significantly decreases fasting
The microbiota are in symbiosis with the host but a blood glucose andHbA1c levels in diabetic patients.
number of environmental factors such as diet, med- L. acidophilus La-5 and B. animalis subsp. lactis BB-
ications, antibiotics etc. can lead to dysbiosis. The 12 administration has been evaluated on T2D pa-
imbalance (dysbiosis) has been associated with a tients.There was a significant difference between
number of gastro intestinal diseases. Recently, re- groups concerning mean changes in the HbA1c, TC
searchers have proposed that metabolic disorders and LDL-C levels. In addition, an increase in HDL-C
might result from alteration in gut microbiota com- levels and a decrease in the LDL-C/HDL-C ratio in
position. Dysbiosis has been linked to diseases such the intervention group. A number of other studies
as diabetes, hypertension, dyslipidemia and cardio- have also shown beneficial effects of probiotics in
vascular diseases. diabetics but the studies are small and not very well
designed. Further large well designed studies with
The hypothesis that bacterial endotoxemia may be specific probiotics compositions are required before
an important factor in causation of insulin resistance recommending in routine clinical practice.
and diabetes has been subject of large number of
studies. Higher counts of Clostridium, Bacteroides Obesity is a metabolic disorder. There is a growing
and Veillonella and lower counts of Bifidobacterium evidence that gut microbiota have an important role

GCDC 2017

Listening to Our Gut: Microbiomes and NCD /CVD 249

in obesity. Intestinal microbiota affects host adiposity
and regulates fat storage. Increased Firmicutes and
decreased Bacteroidetes is seen in obese mice as
compared to lean mice. Proportions of Bacteroide-
tes to Firmicutes are significantly and positively as-
sociated with reduction of glucose tolerance. Fecal
microbiota transplantation from lean mice to obese
mice leads to weight loss. There is also evidence in
human that microbiota transplantation from lean to
obese individuals had beneficial effect leading to
weight loss. Large studies are required to ascertain
the beneficial role of microbiota in obesity.

Microbiota of hypertensive patients has been found
to be less rich and less diverse than that of control
subjects. Similar changes in gut microbiota were
observed with the infusion of angiotensin II. Resto-
ration of gut microbiota led to reduction of hyper-
tension. These observations demonstrate that high
blood pressure is associated with gut microbiota
dysbiosis. A systematic review and meta-analysis of
randomized, controlled trials showed that probiotics
consumption changed systolic BP by -3.56mmHg
and diastolic BP by -2.38mmHg in hypertensives
compared to control groups. The duration of studies
included was > 8 wks. and consumption dose was
>1011 colony-forming units. Although the reduction
was modest but the clinical implication was a 22%
reduction in relative risk of cardiovascular mortality,
myocardial infarction or stroke.

The relationship between diet, inflammation, insulin
resistance, and cardiometabolic risk is partly medi-
ated by the composition of intestinal bacteria. Mi-
croorganisms have been found to have a significant
impact on cardiovascular health. They constitute one
of the etiological factors of cardiovascular disease.
Dyslipidemia with increase in total and LDL choles-
terol has also been linked to dysbiosis.A number of
reports have established the beneficial effects of cer-
tain probiotic bacterial strains in reducing total cho-
lesterol, LDL cholesterol and hypertension.

In summary, intestinal microbiota have an important
role in non-communicable diseases and cardio vas-
cular diseases. A better understanding is required
through further research. The composition and dose
of probiotics for therapeutic efficacy for each disease
condition needs to be clearly defined.

Cardio Diabetes Medicine

250 Cardio Diabetes Medicine 2017

Diabetic Dysrhythmias

Dr. Ulhas Pandurangi

Chief: Dept of Cardiac Electrophysiology and Pacing
Arrhythmia-Heart Failure Academy Madras Medical Mission

Abstract DM is recognized as a major cardiovascular risk
factor and its close relationship with cardiovascular
Diabetes mellitus (DM) is the leading cause of car- morbidity and mortality is well established1. Although
diovascular diseases. It is one of the strongest and coronary artery disease and related cardiac events
independent risk factors for cardiovascular morbidi- are the most documented diabetic cardiovascular
ty and mortality. The accelerated atherosclerosis in complications, cardiac electrical system is also an
large arteries and typically in coronary arteries lead important target for diabetic damage. DM is estab-
to ischemic heart disease (IHD) at an early age with lished as an independent risk factor for AF, VA, SCD
more severe sequel. Metabolic abnormalities may and bradyarrhythmias2,3. There has been growing evi-
lead to cardiomyopathy. The increased prevalence dence about the relationship between hypoglycaemic
of IHD and cardiomyopathy leads to increased inci- episodes and ventricular rhythm disorders4,5. The re-
dence of cardiac arrhythmias especially atrial fibril- lationship between DM and arrhythmic disorders is
lation (AF) and ventricular tachyarrhythmia (VA). Di- not fully understood. This article is on overview of
abetic cardiac autonomic neuropathy (DCAN) is in- etiopathogenesis and management diabetic dys-
creasingly recognised as the cause of more frequent rhythmias.
paroxysmal AF episodes and their conversion into
persistent forms. The increased incidence of sudden Diabetes and AF
cardiac death (SCD) due to VA is attributed to a large
extent to DCAN. The increased susceptibility to AF is the most common arrhythmia in clinical practice
resulting in major cardiovascular morbidity and mor-
postural hypotension and syncopal episodes are the tality6. Earlier The Framingham Study and recently a
result of DCAN. The tolerance level of DCAN patients study from Movahed et al7 clearly established that
specifically and DM patients in general towards the DM is a powerful and independent risk factor for the
episodes of more common regular supraventricular development of AF. Although there is no single and
tachycardias may be lower. Acute changes in met- easy explanation, the electrical and anatomical re-
abolic profile during ketoacidosis episodes might modelling atria and increasing incidence of IHD and
trigger arrhythmias. cardiomyopathy in DM seem to be reasons for AF.

In the absence of specific therapy for diabetic dys- Fibrosis in the atrial tissue is the anatomical hallmark
rhythmias general measures including antiarrhythmic of AF with a role in both starting and perpetuation of
drugs, radio frequency ablation (RFA) and devices the arrhythmia and as the fibrosis expands it is more
such as pacemakers and defibrillators are empiri- likely that paroxysmal AF transforms into permanent
cally used. Hypoglycaemia can be a potential trigger or anti arrhythmic resistant type. Kato et al8 showed
for arrhythmias and sugar control needs meticulous that DM related atrial fibrosis has a potential role in
monitoring. Sinus node dysfunction and degenera- starting AF in diabetic rat models. Exaggerated sys-
tion of conduction system leading to symptomatic temic and tissue level oxidative stress seems to be
bradycardia is more common in DM. The implanted the key element in atrial fibrosis related to DM.
devices are more prone for infections.
None­ nzymatic glycosylation of proteins and the end
Introduction products of this pathway (Advanced Glycation End

GCDC 2017

Diabetic Dysrhythmias 251

products; AGEs) interact with their receptors (RAGE) Figure 1 : Potential pathophysiological mechanisms
and upregulate the connective tissue growth factor of atrial fibrillation in DM
(CGTF). This system (AGERAGE) may start or contrib-
ute to atrial fibrosis in diabetic patients via stimula- Diabetes and ventricular arrhythmias
tion of connective tissue growth factor in the atrial
myocardium9. High incidence and extent of atherosclerotic heart
disease in DM leads to high incidence of VA and SCD
Several clinical and electrophysiological studies have inevitably15. Although this close relationship between
demonstrated DCAN to play significant role in the VA, SCDs and DM is mostly based on the extent of
genesis of AF10. coronary artery disease, nonc­ oronary atherosclerotic
processes like diabetic cardiomyopathy DCAN, mi-
Atrial electrical structure is also affected in diabetic crovascular disease, ventricular structural and elec-
patients. Shortened atrial effective refractory period trical changes may play a role in this phenomenon16
(AERP), increased dispersion of AERP, inter and intra (Figure 2).
atrial conduction time, which are the key elements of
atrial electrical remodelling have been documented. A ventricular repolarization anomaly, which is reflect-
Chao et al11 analyzed the detailed threed­ imensional ed by QTc interval prolongation, is associated with
electro anatomic mapping of 228 patients who has high risk of VA. There are several studies showing,
DM or abnormal glucose metabolism (AGM) and un- marked QTc prolongation in diabetic patients17. An-
derwent AF ablation for the first time. Results showed other strong predictor of VA, microvolt T wave al-
that biatrial voltage measurements in DM and AGM ternans (TWA) measurement, has been found to be
group were significantly lower than control group. often abnormal in DM18. Every 1% rise in HbA1c levels
Furthermore these patients also had increased re- is linked with 13 fold higher risk of having TWA and
currence rate of AF in the follow up period. The rela- suboptimal glycemic control is linked with higher risk
tionship between the degree of control of hypergly- of spontaneous VA independent of QTc interval dura-
caemia and the incidence of AF is not clear. While tion. There are studies to suggest that diabetic myo-
fluctuations in the blood glucose level rather than the cardium is vulnerable for electrical instability and can
long-term hyperglycemic environment has been im- be independent from the scarred myocardium areas
plicated for the increase in the incidence of AF in di- from previous ischemic cardiac damages15,17.
abetic patients12 another clinical study failed to show
any correlation between glucose levels, insulin levels,
HbA1c levels and AF onset in DM patients13. Fatemi et
al14 prospectively evaluated the affect of intense gly-
cemic control on incidence of AF in diabetic patients.
Interestingly, they failed to present any association
between incident AF and intense therapy comparing
to standard therapy group. However, their choice of
periodic electrocardiographic testing instead of event
recorders might alter the results in terms of missing
the paroxysmal AF episodes occurring any time be-
sides the time of ECG taken in the clinic.

Overall, DM seems to be acting a pivotal role in gen-
eration and maintenance of AF in diabetic patients.
Specific structural, electrical and electromechanical
alterations in diabetic heart might create fertile sub-
strate for the development of AF. On the other hand,
acute hypo or hyperglycemia changes in electrolyte
levels or acid­base status and autonomic system dis-
tortions may be trigger mechanisms for the arrhyth-
mia (Figure 1). It is clear that there are still knowledge
gaps about the relationship between AF and DM that
warrant further studies.

Cardio Diabetes Medicine

252 Cardio Diabetes Medicine 2017

Figure 2: Mechanisms of ventricular arrhythmias in In an analysis of 3,115 patients presenting with STEMI
DM who underwent primary PCI, High-grade atrioventricu-
lar block (HAVB) (second-degree Mobitz II or third-de-
Diabetes and complete heart blocks: gree atrioventricular block) was present at baseline in
46 patients (1.5%). Diabetes mellitus was one of the
Bundle branch blocks (BBBs) are common conduc- independent predictors of HAVB. Mortality rate was
tion abnormalities in the population. By analysing significantly higher in patients with versus without
14,500 ECGs, Movahed et al.19 found a high preva- HAVB at 1-, and 3-year follow-ups22. The greater risk
lence of bifascicular block (37.5%) in DM patients. of AV blocks in diabetics in setting of STEMI could
Although the prevalence of LBBB was not increased be due to dysautonomic disturbances of the disease
in DM patients, the or the deleterious effects of hyperglycemia on the
conduction system.
presence of LBBB in DM signifies advance cardiovas-
cular disease in this population. A higher mortality Most of the elderly patients have many underlying
rate in patients with BBB has been found in the Fram- systemic diseases and multiple coronary risk fac-
ingham study20. Whether or not the presence of BBB tors. In a paper studying the prevalence of diabetes
in DM contributes to the increased risk of sudden in elderly patients requiring permanent cardiac pace-
death in this population requires further investigation. maker insertion, there were more number of diabetic
population (11.1%). DM conferred an excessive risk of
The prevalence of high-degree atrioventricular (AV) 1.34 (p<0.01) for permanent pacemaker implantation
block in DM patients appears to be significantly high- in the elderly23.
er than that of the normal population. Podlaha et al.21
studied 258 patients with pacemakers retrospective- In a study of the adult individuals with DM (2006
ly. Second- or third-degree AV block was present in patients), age-adjusted CKD prevalence was 38.3%
126 (48.8%) of the 258 patients. DM was found in during 2007–2012. In patients with chronic kidney
127 (49.2%) patients. AV block was significantly more disease with a pacemaker, higher mortality rates
prevalent in DM patients (53.9%) and was indepen- were observed compared with end stage renal dis-
dent of DM-related risk factors for atherosclerosis. ease patients without pacemaker. In 2778 patients
The largest cross-sectional study involving over who were on renal replacement therapy (RRT), 110
800,000 patients was conducted by Movahed et had a pacemaker implanted. Mortality was higher in
al.19 DM was found to be independently associated the pacemaker group averaging 24.3 deaths per 100
with third degree AV block in uni- and multivariant patient-years versus 14.9 deaths per 100 patient-years
analysis with an odds ratio of 3.1 after adjusting for in the RRT population without pacemaker24.
CAD, CHF, smoking and hyperlipidaemia. However
plausible explanations for the increased prevalence Pacemaker therapy in DM
of high-degree AV block in DM patients have been
enunciated yet. There are no published reports or recommendations
for the evaluation of conduction abnormalities in DM
patients. The occurrence of high-degree AV block or
severe bradycardia in the asymptomatic population
is unpredictable, and data for progression of BBB
to high-degree AV block in DM patients are lacking.
There are no indications for routine 24-h Holter mon-
itoring of asymptomatic DM patient at this time. The
presence of autonomic neuropathy appears to be at
least partially reversible with better glycaemic control,
which, in theory, could decrease the risk of arrhyth-
mias in this population.

Treatment with permanent pacemaker insertion for
high-grade conduction abnormalities in DM patients
should follow the same guidelines as in a non-diabet-
ic population. Reversible cause of BBB and high-de-
gree AV block has been described in case reports
of DM patients secondary to electrolytes or meta-
bolic abnormalities or ischaemia, which needs to be

GCDC 2017

Diabetic Dysrhythmias 253

ruled out and treated before considering permanent geneities in atrial and ventricular repolarization, the
pacemaker insertion. The most certain indications extend of myocardial damage, scar formation, auto-
for permanent pacing include the following: Symp- nomic system distortion, glucose fluctuations as well
tomatic bradycardia due to sinus node dysfunction as structural and electrical alterations have been well
(sick sinus syndrome), Symptomatic chronotropic identified. The causal pathophysiological and elec-
incompetence, Second- or third-degree AV block in trophysiological mechanisms and effect of specific
asymptomatic awake patients in sinus rhythm result- therapies however are warranted in further studies.
ing in periods of asystole longer than 3.0 seconds
or ventricular rates less than 40 beats per minute, References:
Second -or third-degree AV block in asymptomatic
awake patients in atrial fibrillation resulting in pauses 1. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and
of at least 5 seconds, Neurocardiogenic syncope, in mortality in diabetics in the Framingham population. Sixteen year
the setting of chronic bifascicular block for advanced follow-up study. Diabetes 1974; 23: 105-111
second-degree AV block or intermittent third-degree
AV block or Type II second-degree AV block or alter- 2. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA.
nating bundle branch block25. Independent risk factors for atrial fibrillation in a population-based cohort.
The Framingham Heart Study. JAMA 1994; 271: 840-844
The implant of defibrillators and cardiac resynchro-
nization devices should also follow the same indica- 3. Huxley RR, Filion KB, Konety S, Alonso A. Meta-analysis of cohort and
tions as for the normal population. Indications for im- case-control studies of type 2 diabetes mellitus and risk of atrial brillation.
plantable cardioverter-defibrillator (ICD) implant can Am J Cardiol 2011; 108: 56-
be divided into 2 broad categories: secondary pro-
phylaxis against sudden cardiac death and primary 4. Stahn A, Pistrosch F, Ganz X, Teige M, Koehler C, Bornstein S, Hanefeld
prophylaxis. An ICD is recommended as therapy in M. Relationship between hypoglycemic episodes and ventricular arrhyth-
survivors of cardiac arrest due to VF or hemodynam- mias in patients with type 2 diabetes and cardiovascular diseases: silent
ically unstable VT. ICD implantation is appropriate for hypoglycemias and silent arrhythmias. Diabetes Care 2014; 37: 516-520
primary prophylaxis for LVEF <35% and NYHA class I
to III symptoms26. The SCD Heft trial (23) showed that 5. Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E, Hanefeld M.
in patients with NYHA class II or III CHF and LVEF of Risk of and risk factors for hypoglycemia and associated arrhythmias in
≤35 % amiodarone has no favorable effect on survival, patients with type 2 diabetes and cardiovascular disease: a cohort study
whereas single-lead, shock-only ICD therapy reduc- under real-world conditions. Acta Diabetol 2015; 52: 889-895
es overall mortality by 23 percent. As compared with
placebo, amiodarone therapy was associated with a 6. Ball J, Carrington MJ, McMurray JJ, Stewart S. Atrial brillation: pro le and
similar risk of death and ICD therapy was associated burden of an evolving epidemic in the 21st century. Int J Cardiol 2013;
with a decreased risk of death (hazard ratio, 0.77; 97.5 167: 1807-1824
percent confidence interval, 0.62 to 0.96; P=0.007).
DM was seen in 32% of the placebo and 31% of the 7. Movahed MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a
ICD group. The observed benefit of ICD therapy was strong, independent risk for atrial fibrillation and flutter in addition
similar in both DM and non-DM patients27. Recent to other cardiovascular disease. Int J Cardiol 2005; 105: 315-318
meta-analyses of CRT trials have suggested that the
benefit of CRT is dependent on QRS duration, with 8. Kato T, Yamashita T, Sekiguchi A, Sagara K, Takamura M, Takata S,
a significant benefit associated with CRT in patients Kaneko S, Aizawa T, Fu LT. What are arrhythmogenic substrates in
with QRS ≥150 ms, but not in patients with QRS <150 diabetic rat atria? J Cardiovasc Electrophysiol 2006; 17: 890-894
ms25. Clinical response to CRT is also dependent on
QRS morphology, with the greatest response for pa- 9. Kato T, Yamashita T, Sekiguchi A, Tsuneda T, Sagara K, Takamura
tients with LBBB and QRS ≥150 ms. M, Kaneko S, Aizawa T, Fu LT. AGEs-RAGE system mediates atrial
structural remodeling in the diabetic rat. J Cardiovasc Electrophysiol
CONCLUSION 2008; 19: 415-420

AF and VA are most common form of arrhythmias, 10. Tesfaye S, Boulton AJM, Dyck PJ. Diabetic neuropathies: update on
which lead to cardiovascular complications and mor- definitions, diagnostic criteria, estimation of severity, and treatments.
tality in patients with DM. The incidence of CHB and Diabetes Care 2010;33(10):2285–93.
bifascicular blocks are higher in DM. The risk of in-
fection of implanted devices is high. Risk factors for 11. Chao TF, Suenari K, Chang SL, Lin YJ, Lo LW, Hu YF, Tuan TC, Tai CT, Tsao
an arrhythmogenic substrate in DM, such as hetero- HM, Li CH, Ueng KC, Wu TJ, Chen SA. Atrial substrate properties and
outcome of catheter ablation in patients with paroxysmal atrial brillation
associated with diabetes mellitus or impaired fasting glucose. Am J Cardiol
2010; 106: 1615-1620

12. Lip GY, Varughese GI. Diabetes mellitus and atrial fibrillation: perspectives
on epidemiological and pathophysiological links. Int J Cardiol 2005; 105:
319-321

13. Huxley RR, Alonso A, Lopez FL, Filion KB, Agarwal SK, Loehr LR, So-
liman EZ, Pankow JS, Selvin E. Type 2 diabetes, glucose homeostasis
and incident atrial brillation: the Atherosclerosis Risk in Communities
study. Heart 2012; 98: 133-138

14. Fatemi O, Yuriditsky E, Tsioufis C, Tsachris D, Morgan T, Basile J,
Bigger T, Cushman W, Goff D, Soliman EZ, Thomas A, Papademetriou
V. Impact of intensive glycemic control on the incidence of atrial fibril-
lation and associated cardiovascular outcomes in patients with type 2

Cardio Diabetes Medicine

254 Cardio Diabetes Medicine 2017

diabetes mellitus (from the Action to Control Cardiovascular Risk in
Diabetes Study). Am J Cardiol 2014; 114: 1217-1222
15. Balkau B, Jouven X, Ducimetière P, Eschwège E. Diabetes as a risk
factor for sudden death. Lancet 1999; 354: 1968-1969
16. Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D’Agostino RB, Wilson
PW, Savage PJ. Trends in cardiovascular complications of diabetes. JAMA
2004; 292: 2495-2499

17. Cardoso CR, Salles GF, Deccache W. Prognostic value of QT interval pa-
rameters in type 2 diabetes mellitus: results of a long-term follow-up
prospective study. J Diabetes Complications 2003; 17: 169-178
18. Molon G, Costa A, Bertolini L, Zenari L, Arcaro G, Barbieri E, Targher
G. Relationship between abnormal microvolt T-wave alternans and poor
glycemic control in type 2 diabetic patients. Pacing Clin Electrophysiol
2007; 30: 1267-1272
19. Movahed M-R. Diabetes as a risk factor for cardiac conduction defects: a
review. Diabetes, Obesity and Metabolism, 9, 2007, 276–281
20. Schneider JF, Thomas HE Jr, Sorlie P, et al. Comparative features of newly
acquired left and right bundle branch block in the general population: the
Framingham study. Am J Cardiol 1981; 47: 931 940
21. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for
the management of heart failure: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines. Circulation. 2013;128:e240–327
22. Steinberg BA, Al-Khatib SM, Edwards R, et al. Outcomes of implantable
cardioverter-defibrillator use in patients with comorbidities: results from a
combined analysis of 4 randomized clinical trials. JACC Heart Fail. 2014
Dec;2(6):623-9
23. Podlaha R, Falk A. The prevalence of diabetes mellitus and other risk
factors of atherosclerosis in bradycardia requiring pacemaker treatment.
Horm Metab Res Suppl 1992; 26: 84–87
24. Kosmidou I, Redfors B, Dordi R, Dizon JM, McAndrew T, Mehran R, Ben-Ye-
huda O, Mintz GS, Stone GW. Incidence, Predictors, and Outcomes of
High-Grade Atrioventricular Block in Patients With ST-Segment Eleva-
tion Myocardial Infarction Undergoing Primary Percutaneous Coronary
Intervention (from the HORIZONS-AMI Trial). Am J Cardiol. 2017 May
1;119(9):1295-1301

GCDC 2017

Cardio Diabetes Medicine 2017 255

Cardiac Complications in
Diabetic Ketoacidosis

Dr. Sankar, MD (Gen).,

Senior Assistant Professor, Department Of General Medicine,
Thoothukudi Medical College Hospital

ABSTRACT • Osmolality : 300 -320

Diabetic ketoacidosis (DKA) is a serious medical • Plasma ketones : ++++
emergency requiring hospitalisation. DKA consists of
the triad of hyperglycemia, ketosis and acidosis. Sev- • Sodium bicarbonate : <15 mEq/L
eral cardiovascular complications are associated with
ketoacidosis as a result of electrolyte imbalances in- • Arterial pH : 6.8 - 7.3
cluding arrhythmias ECG changes, ventricular tachy-
cardia and cardiac arrest which can be prevented • Arterial P CO2 : 20-30 mmHg
by appropriate treatment. Cardiopulmonary compli-
cations such as pulmonary oedema and respiratory • Anion gap [Na (Cl + HCO3)] : increased
failure have also been seen with DKA.
Clinical features / manifestations of DKA :
Acute myocardial infarction can predispose patients
with diabetes to ketoacidosis and worsen their car- SYMPTOMS
diovascular outcomes.
• Nausea / vomiting
DKA is considered in individuals with type 1 or type • Thirst / polyuria
2 diabetes mellitus , severe hyperglycemia> 16.7 • Abdominal pain
mmol/L (300 mg/dL) and ketones are indicators • Shortness of breath
of DKA associated with symptoms such as nausea
,vomiting or abdominal pain. PHYSICAL FINDINGS

Blood measurement of beta hydroxy butyrate is pre- • Tachycardia
ferred over urine testing with nitroprusside based as- • Dehydration / hypotension
says that measures only acetoacetate and acetone. • Tachypnoea
DKA was formerly considered as a hallmark of type • Kussmaul respiration
1 DM but also occurs in individuals who lack immu- • Respiratory distress
nologic features of type 1 DM (type 2 DM). • Abdominal tenderness
• Lethargy / obtundation
DKA is associated with absolute or relative insulin • Cerebral oedema / possibly coma
deficiency, volume depletion and acid base abnor-
malities.

Laboratory values of DKA : Precipitating events :

• Glucose : 13.9 - 33.3 mmol/L 0R 250 -600 • Inadequate insulin administration

mgs/dl • Infection (pneumonia / UTI / gastroenteritis/sep-
sis)
• Sodium : 125 -135mEq/L
• Infarction(cerebral/coronary / mesenteric/periph-
• Potassium : normal to increased eral)

Cardio Diabetes Medicine

256 Cardiac Complications in Diabetic Ketoacidosis

• Drugs (cocaine) low levels of insulin. By 12 hours of treatment with
fluids and insulin , the extracellular potassium can
• Pregnancy shift intracellularly causing hypokalemia. Serial ECG’s
would be helpful in early detection of hypokalemia
DKA consists of the triad of hyperglycemia , keto- or hyperkalemia.
sis and acidosis. Cardiovascular complications is
increased in individuals with type 1 and type 2 DM. Hypokalemia is associated with ECG abnormalities
There has been little change in the mortality rate as- and cardiac arrhythmias. The most common and the
sociated with DKA despite great improvements in our earliest ECG finding in hypokalemia is a prominent U
understanding of its pathophysiology and treatment. wave. ST depression and T wave inversion can also
There are various cardiovascular complications in occur resembling myocardial ischemia. The most
DKA secondary to electrolyte disturbance and cate- common cardiac arrhythmias are atrial premature
cholamine release. DKA typically manifest as loss of contractions , atrial tachycardia with or without AV
5-8 litres of water , 400 -700 mEq of sodium, 250 block , SVT and ventricular premature contractions.
-700 mEq of potassium and 30-50 mEq of magne- Less common arrhythmias are AV junctional tachy-
sium. cardia or escape rhythm and AV block.

The cardiovascular problems in DKA include : Hyperkalemia occurs in the initial stages of DKA. A
potassium concentration of 5.5-7.5mEq/L , there is a
-- Arrhythmia due to electrolyte imbalance tall tent shaped peaked T wave which is often sym-
metrical with a narrow base and is best seen in leads
-- Adverse effects of acidosis ll ,lll and V2 to V5.

-- Acute myocardial infarction At potassium concentrations of 7.5 -10 mEq/L there
is a reduction in amplitude of P wave , prolongation
-- Pulmonary oedema of PR interval . ST segment depression and disap-
pearance of P wave.
ARRHYTHMIAS IN DKA
At leves above 10-12 mEq/L the QRS complex uni-
DKA results in electrolyte imbalance especially re- formly widens. Potassium concentrations above 12
duction in potassium , magnesium and phosphorus mEq/L , ventricular tachycardia or fibrillation, sine-
which can results in cardiovascular complications if wave , slow ventricular escape rhythm or ventricular
not carefully corrected. stand still occurs.

Cardiovascular complications of electrolyte imbal- Intraventricular conduction defect is usually non spe-
ance : cific but patterns resembling RBBB , LBBB or LPHB
can also occur.
Electrolyte Imbalance Potential Complications
Hypokalemia Occasionally in DKA , the ECG changes due to hy-
Hyperkalemia Arrhythmia , cardiac arrest perkalemia can mimic acute myocardial infarction viz
tall T wave , QRS widening and bundle branch block.
Hypomagnesemia ECG changes , ventricu- Treatment of hyperkalemia reverses these changes.
lar tachycardia, ventricular
Hypophosphatemia fibrillation Magnesium levels should also be monitored close-
ly. Hypomagnesemia can exacerbate potassium loss
Decreased respiration thus causing persistent hypokalemia. Magnesium also
low oxygen saturation ex- serves as muscle relaxant, hypomagnesemia can
acerbating potassium loss result in decreased respiration and low oxygen sat-
uration which worsen the situation in individuals with
Altered mental status, hy- underlying asthma or COPD.
poventilation , cardiopul-
monary arrest An additional electrolyte imbalance that may occur
is elevated phosphorus levels. The normal levels of
Potassium deficit is one of the most important elec- phosphorus are 2.5 to 4.5 mg/dl. Infact there have
trolyte imbalance seen in DKA , as it can lead to fa- been multiple case reports of complications due to
tal arrhythmias. Normal serum range of potassium drastic reduction in phosphorus. Depleted phospho-
is 3.5 to 5mEq/L. serum levels <3 mEq/L can result rus levels can also results in skeletal muscle weak-
in arrhythmias and cardiac arrest whereas levels ness and hypoventilation, leading to cardiopulmo-
>5.5mEq/L can cause ECG changes with subsequent nary arrest.
ventricular tachycardia or fibrillation.

Initially potassium levels elevated due to intracel-
lular shift to the surrounding plasma secondary to

GCDC 2017

Cardio Diabetes Medicine 2017 257

Effect of acidosis in DKA: abnormal blood viscosity all of which are especially
prevalent in diabetes. DKA complicating acute myo-
The effect of acidosis on heart depends upon the cardial infarction increases mortality which may ap-
pH Level. During mild acidosis (pH 7.2-7.35) catechol- proach 85%. On the other hand acute myocardial in-
amine release is increased which is compensated by farction can be one of the major precipitating factors
increased inotrophy, chronotrophy , cardiac output for DKA along with infection, omission or inadequate
and peripheral vascular resistance. insulin and intercurrent illness.

Once the Ph level drops below 7.2 , the H+ ions have BULLET POINTS
a direct cardiac depressant action. This ultimately
leads to reduced cardiac output and potentially se- • Diabetic Ketoacidosis consists of the triad of hy-
vere shock. perglycemia, ketosis and acidosis

DKA and pulmonary oedema : • DKA is associated with absolute or relative insulin
deficiency , volume depletion and acid base ab-
Pulmonary oedema in the absence of left ventricu- normalities
lar failure has been reported in DKA. Arterial vaso-
dilation in the periphery as well as central venous • Cardiovascular complications in DKA are second-
constriction can be present during ketoacidosis and ary to electrolyte imbalance and catecholamine
this vasoconstriction could aid in the development of release
pulmonary oedema.
• In DKA most important electrolyte abnormality is
The aetiology may be pulmonary vascular microangi- seen with potassium which can lead to ECG ab-
opathy seen in diabetes. normalities , cardiac arrhythmias and even cardiac
arrest
Alveolar ventilator compensation is seen in DKA ,
which may precipitate low oxygen saturation and • In acidosis, pHlevel drops below 7.2 will leads to re-
acute respiratory distress syndrome, especially in duced cardiac output and potentially severe shock
those with underlying respiratory disease or acute
respiratory infections. • In DKA insulin deficiency and high levels of ke-
tones and free fatty acids inhibits glucose uptake
Vigorous fluid therapy can precipitate this condition. by the cells and thus deprives the myocardium of
energy utilisation during ischemia
DKA and acute myocardial infarction :
• Pulmonary oedema in DKA may be due to pulmo-
Acute myocardial infarction is not only increased in nary vascular microangiopathy
frequency in diabetes but is also associated with
morbidity and mortality. REFERANCE :

Under normal conditions 60-90 % of myocardial en- 1. DuBose TD Jr. Acidosis and alkalosis. In: Kasper D, Fauci A, Stephen Haus-
ergy requirement is met by oxidation of free fatty ac- er S, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New
ids. During ischemia, the heart shifts from aerobic to York, NY: McGraw-Hill; 2015. Accessed October 6, 2015.
anaerobic metabolism and thus uses glucose instead
of fatty acid as primary fuel. 2. Kaufman DC, Kitching AJ, Kellum JA. Acid-base balance. In: Hall JB,
Schmidt GA, Kress KP, eds. Principles of Critical Care. 4th ed. New York,
In DKA insulin deficiency and high levels of ketones NY: McGraw-Hill; 2015.
and free fatty acids inhibits glucose uptake by cells
and thus deprives the myocardium of energy utilisa- 3. Kishore P. Diabetic ketoacidosis. Merck Manual Professional Version. June
tion during ischemia. In DKA there is increased pro- 1, 2014. .Accessed January 20, 2016.
duction of free radicals which enhance further dam-
age to myocardium. An excess of catecholamines 4. Jacoby R, Nesto R. Acute myocardial infarction in the diabetic pa-
reduce the insulin secretory reserve and causes lip- tient: pathophysiology, clinical course and prognosis. J Am CollCardiol.
olysis and increased myocardial uptake of free fatty ;20:736-744.
acids which are toxic to myocardial cells.
5. Gandhi MJ, Suvarna TT. Cardiovascular complications in diabetic ketoac-
The relationship between diabetes and infarction is idosis. Int J DiabDev Countries. 1995;15:132-133. http://diabetes.org.in/
related mainly to the development of atherosclero- journal/1995_oct-dec/article5.pdf. Accessed October 6, 2015.
sis and plaque rupture. It is well known that factors
leading to atherosclerosis and plaque rupture include 6. Braunwald’s heart disease a textbook of cardiovascular medicine volume
hyperlipidemias, hypertension, hyperinsulinemia and II mann.zipes.libby.bonow

Cardio Diabetes Medicine

258 Cardio Diabetes Medicine 2017

Role of Oxygen Insufficiency
in the Onset & Development of
Vascular Complications of Diabetes

Dr. V.N. Rajasekaran, MD PhD; DTM&H
Dr. R. Sudhir, DNB (General Medicine)

ABSTRACT MECHANISMS OF VASCULAR
COMPLICATIONS
Diabetes mellitus is a chronic metabolic disorder,
which when not controlled adequately, is compli- Some of the most studied mechanisms include in-
cated by damage to several organs, primarily due creased polyol pathway flux causes excessive accu-
to dysfunction and changes in the vascular tree. mulation of sorbitol causing a raised osmotic stress
Vascular changes, both micro- and macro-vascular, on tissues causing Advanced Glycation End prod-
are influenced by several factors. Hypoxia has been ucts. Metabolism of the excess sorbitol to fructose.
quoted as a significant factor in the onset and devel- produces decreased availability of reduced NADH
opment of these vascular complications. This article and alters the NADH/ NAD+ ratio, essential factors
briefs on the possible and confirmed mechanisms by in many redox reactions, thereby inducing a state
which hypoxia as a result of hyperglycemia induced of pseudohypoxia, wherein essential NADH is not
destabilization of the vascular milieu, brings about available for mitochondria for other metabolic cas-
the vascular complications in patients with diabetes cades, This leads to reduced levels of Glutathione,
mellitus and its clinical implications. NO and myo-inositol , There may also be an ath-
eroscelortic plaque obstruction causing a state of
COMPLICATIONS OF DIABETES true hypoxia, further aggravating the problem. Hy-
perglycemia induced activation of the diacylglycerol
Complications involving the end organs are the ma- (DAG)/protein kinase C (PKC) pathway alters vascu-
jor cause of morbidity and mortality in patients with lar permeability,contractility, extra cellular matrix, cell
diabetes. Microvascular complications include reti- growth, angiogenesis, leucocyte adhesion and cyto-
nopathy, nephropathy and neuropathy, are leading kine production. Reactive Oxygen Species induced
causes of blindness, end-stage renal disease and Oxidative stress and its subsequent casade causes
various painful neuropathies; whereas macrovascu- vascular dysfunction Genetic factors also have been
lar complications encompass atherosclerosis related suggested as important risk markers for developing
diseases, such as coronary artery disease, peripher- diabetic complications3. It is thus evident that there is
al vascular disease and stroke1. Two large studies, a complex interplay of factors in the pathogenesis of
the Diabetic Control and Complications Trial (DCCT) vascular dysfunction leading to tissue hypoxia on a
and the United Kingdom Prospective Diabetes Study metabolic level which when combined with mechani-
(UKPDS) clearly showed that intensive control of hy- cal obstruction in the form of atherosclerotic plaques
perglycemia could reduce the progression of diabetic causes major organ damage.
microvascular complications. These clinical observa-
tions indicate that hyperglycemia is a major factor ENDOTHELIAL DYSFUNCTION
responsible for the pathogenesis of diabetic compli-
cations. In contrast, it is known that multiple factors, The endothelium is a monolayer of cells covering the
such as fatty acid, lipid, insulin resistance, inflamma- vascular lumen. The importance, this cell layer is now
tory cytokines in addition to hyperglycemia induced gaining recognition, and now it is known to play vi-
derangement of various metabolic pathways interact, tal roles in maintaining vascular homeostasis by its
increasing the risk for atherosclerosis in diabetes2,3. paracrine, endocrine and autocrine functions, Endo-

GCDC 2017

Role of Oxygen Insufficiency in the Onset & 259
Development of Vascular Complications of Diabetes

thelium-derived hyperpolarization factor (EDHF), ni- ISCHEMIC PRECONDITIONING
tric oxide (NO) and prostacyclin (PGI2),serve to dilate
the vessel and confer anti-proliferative effects. While Ischemic preconditioning (IPC) or postconditioning
endothelin-1 (ET-1), angiotensin II and reactive oxygen (Ipost) is proved to efficiently prevent ischemia/
species (ROS) are those that exert vasoconstrictor ef- reperfusion injuries. Mortality of diabetic patients
fects. Endothelial cells also produce antithrombotic with acute myocardial infarction was found to be 2–6
(NO and PGI2  both inhibit platelet aggregation) and folds higher than that of non-diabetic patients with
prothrombotic molecules [von Willebrand factor, same myocardial infarction, which may be in part due
which promotes platelet aggregation, and plasmin- to diabetic inhibition of IPC- and Ipost-mediated pro-
ogen activator inhibitor-1 (PAI-1), which inhibits fibri- tective mechanisms8,9. It been demonstrated that dia-
nolysis]4. betes may alter both sarcolemmal and mitochondrial
K-ATP channels and then alter mitochondrial func-
Endothelial dysfunction causes shift in vasculature tion10. The oxidative stress due the altered availabity
toward reduced vasodilation, a proinflammatory of redox enzymes aggravates cellular injury.
state, and prothrombic state. Free radicals can dis-
rupt the balance of NO, damaging the endothelium, CLINICAL IMPLICATIONS
aggravating the dysfunction and promoting athero-
sclerosis. Thus setting off a vicious cycle,with wors- Retinopathy onset and progress is by high oxidative
ening imbalance, resulting in widespread disease5. stress and hyperglycemia induced pseudohypoxia ,
triggering a casdae of activity causing leaking of the
CHANGES IN HYPOXIA INDUCIBLE blood vessels, recruitment of VEGF, causing prolifer-
FACTOR ation of new blood vessels, which are prone to hae-
morrhage due to their fragility.
Hypoxia-inducible factor-1 (HIF-1) is responsible for
activating the genes encoding glucose transporters, Early stages of nephropathy, characterized by hyper-
glycolytic enzymes, mitochondrial enzymes that make filtaration increases the load on SGLT channels11 and
metabolism more efficient under hypoxic conditions causes increased oxygen consumption in addition
.It controls various phenomena including growth, sur- to prevalence of the other factors discussed earlier,
vival, angiogenesis, glucose metabolism.There is evi- causing chronic tubulointerstitial injury progressing
dence to suggest that a high osmotic stress inhibits to ESRD.
HIF transcription Excessive Reactive Oxygen Species
present in hyperglycemic states induces a conforma- Endoneural Hypoxia as a result of reduction in nerve
tional change in the P300 component of HIF-1 due blood flow and increased endoneural vascular resi-
to the glycolytic metabolite methyglyoxal. P300 is a tance causes progressive diabetic polyneuropathy.
functional component attached to HIF-1-beta. This
conformational change results in modification of the Micro vascular diseases accelarates atherosclerosis,
transcriptional property of HIF-15,6. through processes we have just reviewed. Combined
with the lose of Ischemic preconditioning, the impact
of hyperglycemia and hyperlipidemia causes a sig-
nificantly higher mortality and morbidity in diabetic
individuals.

Thus, control of hyperglycemia appears to be the
sheet anchor on which our efforts to reduce the com-
plications of diabetes rest upon.

Hypoxia, at least in part through activation of the REFERENCES
hypoxia inducible factor 1 (HIF-1) α-related pathways,
controls all steps of the postischemic revasculariza- 1. Fowler MJ. Microvascular and macrovascular complications of diabetes.
tion process. Recent studies uncover that destabiliza- Clinical Diabetes 2008;26(2):77-82.Chawla A, Chawla R, Jaggi S. Micro-
tion of HIF-1 is most likely the event that transduces vasular and macrovascular complications in diabetes mellitus: Distinct or
hyperglycemia into the loss of the cellular response continuum? Indian J EndocrinolMetab 2016;20(4):546-51.
to hypoxia in most diabetic complications. Downreg-
ulation of HIF-1 in response to hyperglycemia also 2. Kitada M, Zhang Z, Mima A, King GL. Molecular mechanisms of diabetic
seems to account for the decreased collateral growth vascular complications. J Diabetes Investig 2010;1(3):77-89.
triggered by myocardial ischemia in patients with di-
abetes7. 3. Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms
of injury and protective factors. Cell Metab 2013;17(1):20-33.

4. Schmid T, Zhou J, Köhl R, Brüne B. p300 relieves p53-evoked transcription-
al repression of hypoxia-inducible factor-1 (HIF-1). Biochem J 2004;380(Pt
1):289-95.

Cardio Diabetes Medicine

260 Cardio Diabetes Medicine 2017

5. Xenaki G, Ontikatze T, Rajendran R, et al. PCAF is a HIF-1α cofac-
tor that regulates p53 transcriptional activity in hypoxia. Oncogene
2008;27(44):5785-96.

6. Howangyin KY, Silvestre J. Diabetes mellitus and ischaemic diseases. Ath-
erosclerThrombVascBiol 2014 (online).

7. Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning
the diabetic heart. Diabetes 2005;54(8):2360-4.

8. Yin X, Zheng Y, Zhai X, Zhao X, Cai L. Diabetic inhibition of precondition-
ing and postconditioning mediated myocardial protection against ischemia/
reperfusion injury. Experimental Diab Res 2012;article ID 198048.

9. A. Hassouna, M. Loubani, B. M. Matata, A. Fowler, N. B. Standen, and
M. Galiñanes, “Mitochondrial dysfunction as the cause of the failure to
precondition the diabetic human myocardium,” Cardiovascular Research,
vol. 69, no. 2, pp. 450–458, 2006.

GCDC 2017

Cardio Diabetes Medicine 2017 261

Heart Rate Variability in Ischemic
Heart Disease and Diabetes

Dr. R. Hari hara Krishnan MD., DM(Cardio).,

Asst.Prof. cardiology,
Stanley medical college Chennai.

INTRODUCTION to-day basis and over periods of days to weeks when
there are no major intervening clinical events.
Evaluation of beat-to-beat heart rate dynamics, as a
noninvasive albeit indirect probe of autonomic ner- AUTONOMIC NERVOUS SYSTEM
vous system function, is of interest from a number of INTERACTIONS WITH CARDIAC RATE AND
basic perspectives with potential translational appli- RHYTHM
cations. For example, a large body of clinical and ex-
perimental evidence that indicates an important role Modulation of heart rate and the autonomic nervous
for the autonomic nervous system in the triggering system: The autonomic nervous system is the pri-
or sustaining of malignant ventricular arrhythmias . mary regulator of heart rate in the presence of sinus
Higher sympathetic activity unopposed by vagal ac- rhythm . The intrinsic sinus node rate at rest (ie, the
tivity promotes arrhythmia in a variety of ways: rate after pharmacologic or surgical denervation of
the sinus node) is 95 to 110 per minute . Under nor-
• Reducing ventricular refractory period and the mal supine resting conditions, there is little efferent
ventricular fibrillation threshold sympathetic neural input, and the concentration of
circulating catecholamines is low; however, there is
• Promoting triggered activity after potentials substantial efferent parasympathetic traffic on the
vagus nerves, which slows the sinus node rate to 60
• Enhancing automaticity to 70 per minute in most adults. Keep in mind that
resting heart rate is determined by both sympathetic
Vagal stimulation opposes these changes and reduc- and parasympathetic tone (ie, the basic firing rate of
es the effects of sympathetic stimulation by prolong- the nerves). Heart rate variability (HRV) measures the
ing refractoriness, elevating the ventricular fibrillation fluctuations in the RR intervals (also referred to as NN
threshold, and reducing automaticity. There are three intervals for presumed sinus beats) related primarily
major noninvasive or minimally invasive assessment to autonomic control
approaches to evaluating the functioning of the au-
tonomic nervous system. Triggering of cardiac arrhythmias and the autonom-
ic nervous system: Both branches of the autonomic
• RR interval (RRI) or heart rate variability (HRV) nervous system have an important role in the trig-
from short-term or longer term monitoring gering or sustaining of malignant ventricular arrhyth-
mias, particularly post-myocardial infarction (MI). This
• Baroreflex sensitivity (BRS) testing relationship partly explains the predictive value of
abnormal HR variability for such events to the ex-
• Bedside autonomic function tests (eg, Valsalva tent that the arrhythmogenesis is a consequence of
maneuver, tilt testing, and other orthostatic chal- alterations in autonomic functioning.
lenges)
The sympathetic nervous system: Chronically in-
The utility of HRV measures for prediction of out- creased sympathetic activity and elevated plasma
come or detection of changes in clinical status de- catecholamines can be found in the setting of myo-
pends on their stability over time. HRV is influenced cardial dysfunction . These alter the electrophys-
significantly by age, race, sex, physical fitness, clini-
cal conditions, and drug treatment, but most 24-hour
HRV appears to be stable when measured on a day-

Cardio Diabetes Medicine

262 Heart Rate Variability in Ischemic
Heart Disease and Diabetes

iologic properties of the myocardium and promote (normal to normal RR) intervals over a 24-hour pe-
arrhythmogenesis, regardless of the mechanism in- riod reflects total HRV, but in the literature SDNN
volved (enhanced automaticity, triggered activity, or is often reported over a brief (often five minutes)
reentry). Some of the arrhythmogenic effects of high measuring period.
sympathetic activity are related to the adverse effects
of tachycardia, such as ischemia, while others result • SDANN in milliseconds - Standard deviation of
from heterogeneity of ventricular repolarization. the average NN intervals for all of the five-minute
intervals in a 24-hour continuous ECG recording.
Increased sympathetic activity can cause tachycar- However, this measure is not meaningful in a brief
dia, which can result in myocardial ischemia, but recording.
myocardial ischemia, independent of the underlying
mechanism, usually increases sympathetic activity • pNN50 and related - Percent NN intervals >50 ms
while decreasing efferent vagal activity. Additional- different from the prior interval is often available
ly, myocardial ischemia triggers a release of norepi- on commercial Holter HRV reports. pNN50 is ex-
nephrine from epicardial sympathetic nerves and an tremely sensitive to uneven beat detection and/
increase in its local myocardial concentrations due or incorrect beat morphology labeling.
to the high extracellular potassium concentrations
in the ischemic regions, resulting in regional depo- • rMSSD in milliseconds - Root mean square of dif-
larization and repolarization, which is an important ferences between successive NN intervals; essen-
precondition for the development of reentrant activity tially the average absolute value of the change in
and the precipitation of ventricular fibrillation NN interval between beats. rMSSD is also sensi-
tive to uneven beat detection and/or incorrect beat
The parasympathetic nervous system: The parasym- morphology labeling.
pathetic nervous system, through vagal innervation,
may exert important antiarrhythmic effects by reduc- Frequency domain HRV
ing the heart rate and counteracting the proarrhyth-
mic effects of sympathetic nervous system activity • Total power (TP) in ms2 – TP captures the total vari-
. Furthermore, the parasympathetic nervous system ance in HRV.
plays a large role in regulating the inflammatory re-
sponse, and RR variability is inversely related to the • Ultra-low frequency power (ULF) in ms2 – ULF cap-
production of many inflammatory markers tures the magnitude of underlying rhythms in heart
rate at frequencies of every five minutes to once in
 HRV METHODOLOGY, DEFINITIONS, AND 24 hours.
NORMAL VALUES — 
• Very low frequency power (VLF) in ms2 – VLF cap-
Heart rate variability (HRV) is derived from intervals tures the magnitude of underlying oscillations in
between normal heart beats (NNs) and can be quan- the heart rate pattern at frequencies between ev-
tified by many methods : ery 25 seconds and every five minutes (0.003 to
0.04 Hz).
• Time domain measures
• Low-frequency power (LF) in ms2 – LF captures the
• Frequency domain measures magnitude of heart rate oscillations in the range of
three to nine cycles per minute (0.04 to 0.15 Hz).
• Heart rate turbulence
• High-frequency power (HF) in ms2  – HF captures
• Nonlinear/complexity-based measure heart rate oscillations in the range of 9 to 24 cy-
cles per minute, which is the range of typical adult
Time domain HRV respiratory frequencies (0.15 to 0.40 Hz).

• Average NN in milliseconds (and/or heart rate in • LF/HF ratio – (unitless) Often referred to as the
beats per minute) - Not a measure of variability per “sympathovagal” balance.
se, but average heart rate is an important marker
for cardiac autonomic function that is available Heart rate turbulence: Heart rate “turbulence” (HRT)
from any commercial software. Daytime and is a relatively recent HRV parameter that evaluates
nighttime average heart rates are also generally the oscillation (shortening then lengthening) in NN
available, and often hourly heart rates can be intervals associated with a temporary loss of cardi-
obtained as well. ac output in the presence of a ventricular premature
beat (VPB) . Two measures have been calculated,
• SDNN in milliseconds - Standard deviation of NN turbulence onset (TO) and turbulence slope (TS), us-
ing a composite of the responses to all VPBs on the
recording.

GCDC 2017

Cardio Diabetes Medicine 2017 263

CLINICAL USES OF HRV —  and that reduced HRV was associated with disease
severity measures such as NYHA functional class,
• Prediction of risk of cardiac death or arrhythmic left ventricular diastolic dimension, reduced left ven-
events post-myocardial infarction (MI) tricular ejection fraction, and peak O2 consumption
. Prognostically, reductions in HRV have been shown
• Detection and quantification of autonomic neurop- to be independent predictors of overall mortality,
athy in patients with diabetes mellitus mortality from heart failure, sudden cardiac death,
ventricular arrhythmias, and the need for transplant .
Prediction of mortality in the early post-MI period: The
impact of HRV on prognosis post-myocardial infarc- Improvements in HRV are seen with effective heart
tion (MI), initially reported in the era prior to treat- failure therapy (eg cardiac resynchronized therapy
ment with thrombolysis, has also been validated in [CRT]). Patients with improved HRV after CRT have
patients with an MI treated with thrombolytic therapy . been shown to have better outcomes than those in
Patients with reduced indices of HRV measured early whom HRV is not improved.
following an MI (within 14 days) have a three- to four-
fold greater risk of death within three years following Heart rate variability in diabetes patients: Diabetes
an MI. However, the sensitivity of measures like mellitus is one of the main causes of autonomic neu-
SDNN <50 ms as predictors of mortality, originally ropathy. Cardiovascular autonomic neuropathy can
estimated to be about 30 percent, have declined cause abnormalities in heart rate control. Diabetic
simply because improvements in post-MI treatment autonomic neuropathy frequently coexists with oth-
have resulted in markedly fewer patients having er diabetic complications. This complication, which is
SDNN at those levels.. present in 20 – 40% of diabetes patients, is a cause of
increased morbidity and mortality. Cardiac autonom-
Prediction of mortality in the late post-MI period: While ic dysfunction has been diagnosed since the 1970s
reduced HRV in the early post-MI period is clearly by manoeuvres that elicit cardiovascular reflexes. In
associated with a worse prognosis among patients recent years, the use of time-domain and frequen-
from the pre-PCI era, the substantial recovery of HR cy-domain parameters of heart rate variability has
variability within the three months after myocardial been recommended as a reliable and easy method.
infarction, particularly following an inferior infarct, Diabetes caused progressive autonomic dysfunction
raises a question as to whether recovery values for and decreased variability in heart rate. When cardio-
HR variability predict death . Among the 68 place- vascular autonomic neuropathy is identified in a pa-
bo-treated patients entered into the Cardiac Arrhyth- tient with diabetes, there should be aggressive treat-
mia Pilot Study (CAPS) who had 24-hour ECG record- ment to control cardiovascular risk factors, because
ings at baseline and at 3, 6, and 12 months after MI, these may be associated with the development of
there was a substantial increase in all measures of cardiovascular mortality . Insulin therapy can cause
HRV between three weeks and three months . On regression of cardiovascular autonomic neuropathy.
average, recovery of HRV was completed by three In conclusion, patients with diabetes had lower val-
months post-MI; between 3 and 12 months, the val- ues of heart rate variability parameters than healthy
ues were stable for the group as a whole and for controls, and among diabetes patients those with
individual patients. microvascular complications had the lowest heart
rate variability parameters. Patients with microvas-
Patients with stable CHD: An association between cular complications should be followed up more in-
decreased HRV and the presence of significant tensely than others and should be treated with insu-
coronary heart disease (CHD) has been suggested. lin to prevent the progression of cardiac autonomic
Among 470 consecutive patients undergoing elec- dysfunction. Diabetes patients had lower values for
tive coronary angiography, patients with obstructive time-domain and frequency-domain parameters than
CHD (>50 percent stenosis) had significantly reduced controls. Most heart rate variability parameters were
HRV based on five-minute supine measurement, es- lower in diabetes patients with chronic complications
pecially in the low frequency range (180 with versus than in those without chronic complications.
267 ms2 without obstructive CHD) . In a multivariate
analysis using a cutoff of 250 ms2, persons with low SUMMARY AND RECOMMENDATIONS
frequency power below 250 ms2 were at significantly
greater risk of obstructive CHD ,independent of base- • There are three major noninvasive or minimally in-
line Framingham Risk Scores. vasive assessment approaches to evaluating the
autonomic nervous system which provide comple-
Patients with heart failure: Several studies have mentary information about autonomic as well as
shown that patients with heart failure and/or cardio-
myopathy have reduced HRV compared with controls,

Cardio Diabetes Medicine

264 Heart Rate Variability in Ischemic
Heart Disease and Diabetes

non-autonomic regulatory mechanisms in health
and disease: heart rate variability (HRV), baroreflex
sensitivity, and bedside autonomic function tests.
• The autonomic nervous system, including the
sympathetic and parasympathetic nervous sys-
tems, has an important role in the triggering or
sustaining of malignant ventricular arrhythmia.
• HRV (derived from intervals between normal si-
nus beats NN intervals) can be measured by
many methods, which can be categorized as
time domain measures, frequency domain mea-
sures, nonlinear/complexity-based measures, and
heart rate turbulence
• HRV appears to be highly consistent over 24 hours,
despite marked differences among the five-minute
intervals during a day. The same stability in HRV
appears to be true for patients with ventricular ar-
rhythmias, angina, and heart failure.
• HRV has been shown to be significantly decreased,
compared to normal values, among post-myo-
cardial infarction (MI) patients, although there is
considerable interindividual difference in this. This
decreased HRV is a likely a marker for autonomic
dysregulation and likely reflects both decreased
parasympathetic and increased sympathetic activ-
ity. Reduced HRV has also been associated with
worse outcomes in patients with stable coronary
heart disease, heart failure, and diabetes.
• We do not recommend the routine use of HRV
testing based on clinical Holter scanning at the
moment, but we hope that a refinement of the al-
gorithms by which HRV is interpreted can be im-
plemented and HRV will become useful outside of
the clinical trial setting

GCDC 2017

Cardio Diabetes Medicine 2017 265

Hypoglycemia How Critical it is?

Prof. Dr. S. Arulrhaj MD., FRCP., (Glasg.)

Chief Physician and Head Acute Medicine
Sundaram arulrhaj hospitals,Tuticorin

Dr. Aarathy Kannan MD., Dip Diabetes

Physician and Diabetologist

Dr. Manikandan. R & Dr. Vinodh Kumar. A. DNB (Med).,

Abstract: Association (ADA), the American Association of Clin-
ical Endocrinologists (AACE), the Endocrine Society,
-- Hypoglycemic events are associated with the po- and by the Joint British Diabetes Society and Dia-
tential for harm and should be avoided. betes UK . This value is recommended because it
approximates the lower limit of normal postabsorp-
-- Hospitalized patients suffering from hypoglyce- tive plasma glucose concentration and the glycemic
mia, particularly spontaneous hypoglycemia, carry threshold for activation of glucose counter regulatory
a poor prognosis. responses5. The value is practical in that it is higher
than the glycemic threshold for hypoglycemic symp-
-- When hypoglycemia occurs, the cause needs to toms in most patients, allowing time for caregivers to
be elucidated and treatment regimen adjusted ap- respond and prevent a more severe clinical event. It
propriately. also provides some margin for the limited accuracy
of glucose monitoring devices that exists at lower
-- More aggressive insulin regimens appear to be glucose concentrations4 .
beneficial in some patient populations, but should
be individualized. As not all patients experience a correlation between
symptoms and plasma glucose levels, the ADA work-
Introduction shop on hypoglycemia has developed a new classi-
fication of hypoglycemia. This classification is useful
Hypoglycemia is defined by the American Diabetes to better define and better understand hypoglycemic
Association as a blood glucose less than 70 mg/dL, events.
with symptoms of Hypoglycemia which are relived by
Glucose Administration. CLASSIFICATION OF HYPOGLYCEMIA

This may result in a variety of symptoms including Severe hypoglycemia
clumsiness, trouble talking, confusion, loss of con-
sciousness,  seizures, or death1. A feeling of hunger, • An event requiring assistance
sweating, shakiness, and weakness may also be
present. Symptoms typically come on quickly.Defin- Documented symptomatic hypoglycemia
ing a single measurement threshold for hypoglyce-
mia is complex since the physiological thresholds • Symptoms and glucose ≤70 mg/dl (3.9 mmol/l)
vary with age, gender and health status. In addition,
recent hypoglycemic episodes will lower the thresh- Asymptomatic hypoglycemia
old at which patients experience symptoms in re-
sponse to low blood sugar, while poorly controlled • Absence of symptoms and glucose ≤70 mg/dl (3.9
diabetics with chronic hyperglycemia may experience mmol/l)
symptoms at higher glucose levels from relative hy-
poglycemia3. In hospitalized patients, hypoglycemia Probably symptomatic hypoglycemia
unawareness is common and the healthcare pro-
vider should be alerted by a value of blood glucose • Symptoms without documented low glucose ≥70
<70 mg/dl (3.9 mmol/l)1. This level is pragmatic, data mg/dl (3.9 mmol/l)
driven and recommended by the American Diabetes
Pseudohypoglycemia

• Symptoms and glucose ≥70 mg/dl (3.9 mmol/l)

Cardio Diabetes Medicine

266 Hypoglycemia How Critical it is?

PATHOGENESIS OF HYPOGLYCEMIA IN jection were subjected to gel chromatography, and
ICU the fractions obtained were measured by RIA for be-
ta-endorphin. In four healthy subjects, basal plasma
Spontaneous episodes of severe hypoglycemia are beta-endorphin levels were less than 3 to 3.1 pg/ml,
rare during the management of critically ill patients and the levels rose substantially to 47.5 +/- 12.4 pg/
(usually observed in less than 1.5% of patients) and ml (mean +/- SE) 45 min after insulin injection3. Basal
are observed mainly during fulminant hepatic failure plasma beta-endorphin levels in three hyperthyroid
and/or overt adrenal failure during septic shock, es- patients (less than 3 to 3.8 pg/ml) did not seem to
pecially in patients with severe comorbidities (malnu- be different from those in healthy subjects; however,
trition, liver cirrhosis, chronic renal failure)4. Since the the rise after insulin injection tended to be higher in
introduction of the strict glycemic control strategy in cases of hyperthyroidism, with a peak value of 68.5
intensive care units (ICUs),hypoglycemia has become +/- 9.7 pg/ml. Plasma beta-lipotropin and ACTH lev-

els also rose in parallel
with beta-endorphin in
response to insulin-in-
duced hypoglycemia
in both healthy sub-
jects and hyperthyroid
patients4. It would thus
appear that beta-en-
dorphin, like ACTH or
beta-lipotropin, is re-
leased in human sub-
jects by hypoglycemic
stress1. 

a daily concern during the management of critically Prevalence of
ill patients5. Hypoglycemia

Absolute or relative insulin excess, with inadequate Overall prevalence of
or interrupted nutritional support and/or insufficient hypoglycemia among
provision of exogenous glucose, together with fea- medical surgical patients with type2 diabetes (T2DM)
tures of critical illness that limit endogenous glucose treated with insulin ranges from 3%-29%
production and accelerate glucose utilization are the
fundamental causes of hypoglycemia in the ICU2. Upto 1 in 4 patients with diabetes may experience
hypoglycemia during hospital admission.
The occurrence of occasional human errors or inabil-
ity to follow the algorithm because of workload can Upto 20% of patients with diabetes treated with insu-
also represent additional risks for hypoglycemia. Sec- lin or anti- diabetic agents(ADAs) have hypoglycemia
ond, other circumstances contributing to the occur- related symptoms that required Emergency Depart-
rence of hypoglycemia (such as renal and/or hepat- ment evaluation and treatment.
ic failure, adrenal insufficiency, antibiotic treatment
with a quinolone) can be present1. Recognition of Hypoglycemia

βEndorphin is involved in the regulation of insulin Symptoms of hypoglycemia can be divided into ad-
secretion and carbohydrate metabolism in hyper- renergic (rapidly falling and changing glucose levels)
androgenic, hyperinsulinemic women2. To elucidate andneuroglycopenic.
whether insulin-induced hypoglycemia enhances the
release of beta-endorphin in man, plasma extracts The adrenergic symptoms are inversely correlated
obtained from healthy subjects and patients with to the developing rate of hypoglycemia, being most
Graves’ disease before and 45 min after insulin in- pronounced with acute onsets. Adrenergic features,
when present, precede neurobehavioral features,
thus functioning as an early warning system. Inpa-
tient team members must be alert to early adrenergic
hypoglycemia signs and symptoms, including anx-
iety, irritability, dizziness, diaphoresis, pallor, tachy-
cardia, headache, shakiness, and hunger3.

GCDC 2017

Cardio Diabetes Medicine 2017 267

A8 Patient - Days % 6.3 ICU
6 <70 3.7
4 5.7
2 <70 2.1
0
Patient - Days % <60 <50 1.1
B8 Glucose Level, mg/dl <40
6
4 Non - ICU 0.8
2 <40
0 3.3
1.7

<60 <50
Glucose Level, mg/dl

Neuroglycopenic signs occur when the brain’s de- Risk Factors for Hypoglycemia
pendence on glucose, coupled with its limited gly-
cogen stores, results in rapid CNS dysfunction5. If Common Risk Factors Less Common Risk
warning signs are absent or ignored and the blood Factors
glucose level continues to fall, more severe hypogly-
cemia may lead to alteration of mental function that Mismatch of insulin Endocrine deficiencies
proceeds to headache, malaise, impaired concentra- timing, amount, or type (cortisol, growth hor-
tion, confusion, disorientation, irritability, lethargy, for carbohydrate intake mone, or both), non–beta
slurred speech, and irrational or uncontrolled behav- cell tumors
ior, which may be confused with dementia.Notable
CNS dysfunction, including focal seizures, hemiple- Oral secretagogues Ingestion of large
gia, paroxysmal choreoathetosis, and patchy brain without appropriate amounts of alcohol or
stem and cerebellar involvement mimicking basilar carbohydrate intake salicylates
artery thrombosis, has also been reported1. The med-
ullary phase of hypoglycemia, characterized by deep History of severe hypo- Sudden reduction of
coma, pupillary dilatation, shallow breathing, brady- glycemia corticosteroid dose
cardia, and hypotonicity, occurs at a blood glucose
level of ~ 10 mg/dl.6 Most individuals with diabetes General anesthesia or Emesis
never suffer such severe hypoglycemia4 sedation that places
patient in an altered
consciousness

Reduction of oral intake Reduction of rate of intra-
venous dextrose

Signs and Symptoms of Hypoglycemia New NPO status Unexpected interruption
of enteral
Early Adrenergic Symptoms Neuroglycopenic Signs

• Pallor • Confusion Unexpected transport feedings or parenteral
after injection of rapid- nutrition
• Diaphoresis • Slurred speech or fast-acting

• Tachycardia • Irrational or uncontrolled behav- Critical illnesses (hepat- Drug dispensing error
ior ic, cardiac,and renal fail- insulin
ure; sepsis; and severe
• Shakiness • Extreme fatigue trauma)

• Hunger • Disorientation

• Anxiety • Loss of consciousness

• Irritability • Seizures

• Headache • Pupillary sluggishness

• Dizziness • Decreased response to noxious
stimuli

Cardio Diabetes Medicine

268 Hypoglycemia How Critical it is?

Patient Related Others mic episodes should be avoided as it can lead to
trauma from falls or seizures, often extending the
Older age Long duration of diabe- hospital stay.
tes
A number of case reports, mostly in children, have
Impaired hypoglycemia Nil per oral without shown that hypoglycemia can be fatal in 4–10% of
patients with Type 1 diabetes. In the adult population,
awareness change in treatment prolonged or severe hypoglycemia can cause brain
injury, but most cases of fatal hypoglycemia have
Severe illness Food malabsorption: eg been attributed to ventricular arrhythmias, the so-
Coeliac disease, gastro- called ‘dead in bed syndrome’.
enteritis
Recent literature supports the concept that sponta-
Septic shock Drug dispensing error neous, but not necessarily iatrogenic hypoglycemia
is associated with risk of death. Among the major
Mechanical ventilation inpatient trials of intensive glycemic management,
only NICE-SUGAR, a large multicenter trial, reported
Renal failure Drugs an overall increase in mortality with intensive insulin
Hepatic dysfunction Beta blockers therapy1. Also, in a retrospective analysis of patients
Malignancy Quinine with diabetes admitted to the general wards a cor-
Severe trauma Sulphonylureas relation of hypoglycemia with increased mortality
Salicylates was found, but this association held true even at 1
Sulfonamides year postdischarge, implying that hypoglycemia was
Trimethoprim a marker of disease burden rather than a direct cause
of mortality3. By contrast, several studies demonstrat-
Clinical mimics ed a decrease in mortality with intensive insulin con-
trol, while others failed to show any significant as-
• Addison Disease sociation, and two multicenter randomized-controlled
• Adrenal Crisis trials (VISEP and Glucontrol) had to be terminated
• Alcoholism early owing to high rates of severe hypoglycemia,
• Anxiety Disorders but there was no evidence of increased mortality. The
• Cardiogenic Shock only trials carried out in patients with diabetes are
• Hypopituitarism (Panhypopituitarism) the DIGAMI trials that showed a decrease in mortality
• Insulinoma with tight glycemic control at 1 and 5 years follow-up.
• Pseudohypoglycemia The DIGAMI-2 trial failed to show a long-term benefit
with more aggressive insulin regimens as compared
Complications & Consequences with conventional therapy5. For a summary of the re-
sults of inpatient trials on the association between
Hypoglycemia can lead to significant morbidity and hypoglycemia and mortality. A post hoc analysis of
occasional mortality, with recurrent hypoglycemia be- the NICE-SUGAR trial demonstrated attenuated haz-
ing the most common complication2. This places pa- ard ratios after adjustment for baseline characteris-
tients at risk of more severe hypoglycemia risk with a tics and post-randomization factors. They also noted
dose-dependent response, with mortality increasing that the hazard ratio for death was greater (and the
proportionally with the frequency and severity of hy- time to death shorter) among patients who had hypo-
poglycemia4 . Inpatient hypoglycemia is also associ- glycemia not being treated with insulin, as compared
ated with increased cost mainly owing to increased with the patients treated with insulin. These findings
length of stay. support the notion that spontaneous hypoglycemia,
rather than iatrogenic hypoglycemia, is associated
Hypoglycemia can affect cognitive function in adults, with increased mortality3.
although the effects are more significant in children
under the age of 5 years. Large data obtained in Other studies have also questioned whether hypo-
adults during the 18 year follow-up of the Diabetes glycemia is truly a cause of mortality or simply a
Control and Complications Trial (DCCT) showed tran- biomarker of increased disease burden and poor
sient cognitive dysfunction but similar performances prognosis. One study of patients with acute myo-
on cognitive tests between patients with and with- cardial infarction found that hypoglycemia (glucose
out a history of severe hypoglycemia reassuring no <60 mg/dl or 3.3 mmol/l) was a predictor of in-hos-
permanent brain damage3. In hospitalized patients,
short-term cognitive impairment during hypoglyce-

GCDC 2017

Cardio Diabetes Medicine 2017 269

pital mortality but only in patients with spontaneous
hypoglycemia, while iatrogenic hypoglycemia was
not associated with increased mortality. This con-
cept was further supported by a large retrospective
study of hypoglycemia (glucose <70 mg/dl or 3.9
mmol/l) in hospitalized patients, which showed that
only spontaneous hypoglycemia was associated with
increased mortality but not iatrogenic hypoglycemia4.
However, when adjusted for comorbidities, even the
association of spontaneous hypoglycemia and mor-
tality disappeared. These findings imply that in most
cases, hypoglycemia is a biomarker of disease rather
than a direct cause of fatality.
Nevertheless, trials such as NICE-SUGAR raise con-
cern for the effects of iatrogenic hypoglycemia,
leading to changes in the clinical guidelines to be
discussed below. The variable results of these trials
has also raised awareness of a need for glycemic
control to be tailored to patient specific situations,
where younger and healthier patients may benefit
from more intensive glycemic control while older and
sicker patients can be managed with relaxed protocol

The Heart and Hyploglycemia

Frequent Asymptomatic hypoglycemia and increased risk of
arrhythmias in patients with type 2 diabetes

Cardio Diabetes Medicine

270 Hypoglycemia How Critical it is?

Cause of Death in Hypoglycemic Patients • In critically ill patients,capillary blood glucose mea-
sured by finger stick is inaccurate
We obtained information on whether death was relat-
ed to infection and on the proximate cause of death. • The presence of shock, use of vasopressors and
Using a minor modification of the approach adopted upper extremity edema were associated with the
by the NICE-SUGAR trial. we created 5 cause-of-death occurrence of inaccurate readings
categories: (1) neurologic (traumatic and nontraumatic
brain injury both with and without brain death), (2) Types of Hypoglycemia in critical care
cardiovascular (arrhythmia, cardiogenic shock, dis-
tributive [septic] shock and hypovolemic shock), (3) Spontaneous hypogly- Iatrogenic hypoglycemia
respiratory (hypoxic respiratory failure), (4) liver relat- cemia
ed (liver failure), and (5) other.
Occurs in sick hospital- -- Originates from treat-

Risk factor for Mortality in the ICU ized patients with organ ment

Condition Severe Mortality failure, malnutrition, or -- Aggressive glycemic
Hypoglycemia those taking predispos- therapy (usually insu-
0.97 ing medications lin)
1.33
Diabetes 3.07* 1.30* -- Also include drug-to-
2.43* drug interactions,
Septic Shock 2.03*
0.67* -- Patients who develop
Creatinine >3 mg /dl 1.10* 1.14* organ failure while al-
1.03* ready taking anti-dia-
Mechanical 2.11* 2.28* betic agents
Ventilation

Tight glycemia control 1.59*

APACHE II Score 1.07* Hypoglycemia induced mortality

AGE 1.01* • Hypoglycemia induces cardiac death often quoted
as “dead in bed” syndrome
Severe hypoglycemia -
(≤ 40 mg / dl) • Hypoglycemia is associated with QT prolongation
and Re-entrant arrhythmias
Challenges for managing hypoglycemia in
the ICU setting • Decreased baroreflex sensitivity after antecedent
hypoglycemia
• Detection of hypoglycemia is difficult as patients
are unable to communicate • High risk patients

• Glucose concentrations may differ according to -- Diabetes and a history of recurrent hypogly-
the blood sampling site(venous,arterial or capillary cemia
blood)
-- Long standing disease and organ failure

Intensive glycemic control studies showing rates of hypoglycemia and mortality

Study (Reference N Characteristics Definition of Hypogly- Rate of Hypo- Mortality Impact
(% diabetes)
cemia glycemia

Surgical ICU (30) Glucose goal 80-110mg/dL Glucose <40 mg/dL 5% vs. 0.78% 
N=1,548 (13%) vs. “usual care” (≤ 215mg/ arterial blood 43% ICU p=0.01 34%
dL)
Hospital P=0.01

Medical ICU (38) Glucose goal 80-110mg/dL Glucose <40 mg/dL 18.7% vs. 3.1% 
N=1.200 (16.9%) vs. “usual care (≤200mg/dL) arterial blood 9.5% p=0.009 (overall)

(In first 3 days)


Pediatric ICU (39) Normoglycemia vs. conven- Glucose <40 mg/dL 24.9% vs. 1.4% 
N=700 (0.9%) tional therapy (≤ 214mg/dL) (or <30mg/dL for neo- 3% p=0.038
nates) arterial blood

VISEP (41) N=537 Glucose goal 80- 110mg/dL Glucose <40 mg/dL 17% vs. 4.1% 
(30.4%) vs. conventional (≤ 200mg/ (method not docu- Study terminated early
dL) mented)

GCDC 2017

Cardio Diabetes Medicine 2017 271

Intensive glycemic control studies showing rates of hypoglycemia and mortality

GLUCONTROL (42) Glucose goal 80- 110mg/dL Glucose <40mg/dL 8.7% vs. 2.7% 
(method variable)
N=1,101 (18.8%) vs. conventional (140- 180m Study terminat-
ed early
g/dL)

NICE-SUGAR (40) Glucose goal 81- 108mg/dL) Glucose <40mg/dL 6.8% vs. 0.5 
N=6,104 (20%) vs. conventional (≤ 180mg/ (method of testing 2.6% p=0.02 At
dL) variable)
day 90


At day 28

DIGAMI (43) Intravenous insulin and glu- Glucose <54mg/dL 15% vs. 0% 
N=620 (100%) cose for 24 hours followed (method not report- 28% p=0.011 At
by basal-bolus insulin vs. ed)
standard therapy 5 years

DIGAMI 2 (44) Two arms with intravenous Glucose <54mg/dL 12.7% in inten- 
N=1,253 (100%) insulin and glucose for 24 (method not report- sive therapy Between the 3
hours (one more aggressive) ed) vs. 9.6%
followed by basal-bolus in- vs. 1.0% arms
sulin vs. standard therapy

Hypoglycemia in cardiac ICU 6. Atrial fibrillation

Hypoglycemia Causes:- 7. The ECG changes are primarily due to catechol-
• Blood coagulation abnormalities amines and hypokalemia which is the probable
• Inflammation mechanism for “Dead in bed syndrome”.
• Endothelial dysfunction
• Sympathetic nervous system activation MYOCARDIAL EFFECTS DUE TO
HYPOGLYCEMIA:
ECG CHANGES IN HYPOGLYCEMIA:
Myocardial effects are mediated by insulin and epi-
1. Prolongation of QT interval nephrine
2. Tachycardia
3. Ventricular ectopic beats The following are the myocardial effects of hypogly-
4. Changes in heart rate variability cemia:-
5. ST-T changes
• Ejection fraction is increased

• Peak filling rate is increased

• EDV is increased

Cardio Diabetes Medicine

272 Hypoglycemia How Critical it is?

• Prolonged severe hypoglycemia results in depres- -- Follow the treatment for hypoglycemia according
sion of myocardial function and causes LV dys- to the table below.
function.
-- Notify physician for subsequent treatment orders
HEMODYNAMIC CHANGES DUE TO and reassessment of patient’s ability to safely
HYPOGLYCEMIA:- self-manage their insulin pump.

Hemodynamic changes are primarily due to epineph- -- -Initiate seizure precautions for patients with al-
rine tered consciousness.

• Systolic BP is increased If patient on

• Diastolic BP is decreased -- FLUID RESTRICTIONS: recommend glucose gel
for treatment
• Pulse pressure is increased
-- RENAL RESTRICTIONS: recommend glucose gel
• Increase in central aortic pressure for treatment. Avoid orange juice, colas, milk, pea-
nut butter or cheese.
• Heart rate is increased
-- SWALLOWING PRECAUTIONS OR LEVEL ONE
Acute coronary syndrome PUREE DIET: recommend 4 oz of juice with 2 TBSP
thickener
• Moderate hypoglycemia acutely increases the cir-
culating levels of plasminogen activator inhibitor, -- IF PATIENT ON Precose (Acarbose): only use glu-
vascular endothelial growth factor, vascular ad- cose gel to treat hypoglycemia. Treatment with su-
hesion molecules, Interleukin-6 and markers of crose (juice, jelly, pop, sugar) is ineffective.
platelet activation.
Important aspects of management : A
• In T2DM patients with coronary artery disease, Hypoglycemia protocol
hypoglycemic episodes are associated with de-
pressed heart rate variability. Clear definition of hypoglycemia

Treatment: BG < 70 mg/dl (severe hypoglycemia: BG < 40)

If patient on a SUBCUTANEOUS INSULIN PUMP be- Nursing order to treat without delay Document the
comes hypoglycemic, incident

-- Suspend the insulin pump until blood glucose>60 Look for the cause of hypoglycemia and determine
mg/dL. If patient has a change in level of con- if other treatment changes are needed.
sciousness (ranging from confusion to coma), pull
out infusion site to stop insulin administration if Hypoglycemia Protocol: Follow-up
unable to suspend infusion pump.

GCDC 2017

Cardio Diabetes Medicine 2017 273

Conscious patient, no Unconscious patients, at 5. Providing appropriate nutritional requirements
risk of aspiration risk for aspiration
6. Applying systems for eliminating or reducing
Repeat blood glucose Repeat blood glucose medication and treatment errors in hospitalized
test in 15-30 minutes to test in 15 30 minutes patients
evaluate treatment
1. Recognition of precipitating factors
If BG > 70 mg/dl on re- If glucose less than 70
peat, no further treat- mg, repeat treatment This includes delay in the timing of meals or dos-
ment. Repeat treatment age of oral hypoglycemic agents or insulin; errors
if < 70 mg/dl in dosages administered; timing of the medication,
particularly insulin; and the presence of a comorbid-
Provide the patient with Once patient stabilized, ity, such as renal insufficiency, adrenal insufficien-
a meal/ snack within 1 notify physician regard- cy, and pituitary insufficiency, which heightens the
hour of last carbohydrate ing response to treat- risk for hypoglycemia. Self-management by patients
treatment ment, receive further whose diabetes is well controlled as outpatients and
orders/ monitoring pa- who possess the capability of managing their insu-
rameters lin regimen in the hospital, such as those who wear
an insulin pump or who use multiple daily injections
Strategies for Reducing Risk for of glargine and aspart or lispro, can be a means to
Hypoglycemia in Noncritical Care Settings reduce hypoglycemia.1,4

• Avoidance of sliding – scale insulin alone 2.Scheduled insulin therapy

• Use caution in prescribing oral anti-hyperglyce- Although endocrinologists have been warning
mic agents against its use for decades, the regular or rapid-act-
ing analog insulin sliding scale without basal insulin
• Modify outpatient insulin doses in patients treat- replacement remains a common method of attempt-
ed with insulin prior to admission. ing to control hyperglycemia in the hospital.Usually,
out of concern for hypoglycemia, no basal insulin is
Standardize Insulin Therapy to Reduce given, and prandial insulin is given only if the pre-
Errors meal blood glucose is elevated. Predictably, this ap-
proach does not work. If no insulin is given before a
• Single insulin infusion concentration meal, the blood glucose level rises substantially and
• Single insulin infusion protocol remains elevated at the time of the next meal. Then,
• Guidelines for transitions: IV to SC a large dose of regular, lispro, or aspart insulin is
• Guidelines for special situations given, which could cause hypoglycemia, particularly
if administered at bedtime without a meal. Standard
• Enteral nutrition insulin sliding scales are ineffective, carry the risk
• Parenteral nutrition of hyperglycemia and hypoglycemia, and generally
• Patient transportation and other handoffs should be avoided.
• Hypoglycemia: BG <70 mg/dL
3.Inpatient use of oral agents
Prevention
Oral agents should not be used by inpatients who
Balancing glycemic control by preventing hyperglyce- are too ill to maintain adequate caloric intake or who
mia and hypoglycemia is key for providing optimum are on NPO status because of illness or planned pro-
care of individuals with diabetes. The inpatient team cedures. Secretagogues can cause hypoglycemia,
can prevent or reduce hypoglycemic events by alpha glucosidase inhibitors are ineffective without
carbohydrate intake, and metformin puts patients at
1. Recognizing precipitating factors or triggering risk who are renal compromised or in heart failure.
events; Thiazolidinediones (TZDs) should be discontinued
in patients with Class III or Class IV heart disease,
2. Ordering appropriate scheduled insulin or anti-di- although the lingering effects of TZDs last several
abetic oral agents; weeks.5

3. Monitoring blood glucose at the bedside; A common error in this population of patients is the

4. Educating patients, family, friends, and staff
about symptom recognition and appropriate
treatment;

Cardio Diabetes Medicine

274 Hypoglycemia How Critical it is?

BG less than 70 mg/dLand Patient Unconscious or Uncooperative or NPO

Immediate Action/Treatment Repeat Follow-up Treatment

*Staff to remain with patient Repeat BG and retreat q15 min until If patient NOT NPO or when able to
BG > 70 mg/dL without symptoms swallow, feed patient carbohydrate
DO NOT WAIT FOR LAB CONFIR- to avoid recurrent hypoglycemia.
MATION OF BG BEFORE TREAT- or BG > 80 mg/dL.  If more than 1 hr until next meal/
ING Glucagon : should only be repeated
x1 snack, also give 15 gms of carbo-
 If IV access: Give 50 ml (25 Add order to check BG at 0200 hydrate*:
one time * 3 graham crackers OR 6 saltine
grams)D50 IVP over 2-5 minutes crackers OR 8 oz skim milk.

 If no IV access AND glucose

<60 mg/dL: Give 1 mg Glucagon
SC x1 and start IV access STAT.
Patient must be turned on their  If more than 2 hrs until next
side to prevent aspiration.Note: meal/snack. also add protein:
Glucagon may be ineffective in - 1/2 sandwich OR
patients with inadequate glyco- - 3 graham crackers with one
gen stores such as children or TBSP peanut butter

newly diagnosed adults IF NPO OR CONTINUES TO BE UN-

CONSCIOUS/UNCOOPERATIVE:

• IF IV ACCESS: Verify IV fluids
contain 5% dextrose. Recheck
BG in 1 hour.

• IF NO IV ACCESS: Obtain MD or-
ders for IV fluids with dextrose.
Check BG in 1 hour. Then follow
treatment per IV access.

Notify provider responsible for glucose
management ASAP, and certainly PRIOR to
administering the next insulin or oral diabe-
tes agent for medication and glucose mon-
itoring orders.

BG 45 mg/dL and Patient Conscious, Cooperative, and Able to Swallow

Immediate Action/Treatment Repeat Follow-up Treatment

Staff to remain with patient Repeat BG and retreat  If more than 1 hr until next meal/snack,
DO NOT WAIT FOR LAB CONFIR- q15 min until BG > 70 also give 15 gms of carbohydrate*:
MATION mg/dL without symp-
OF BG BEFORE TREATING toms or BG > 80 mg/dL. * 3 graham crackers OR
* 6 saltine crackers OR
* 8 oz skim milk

Give 30 Grams carbohydrate: Add order to check BG  If more than 2 hrs until next meal/snack.
 8 oz juice or regular pop OR at 0200 one time also give 15 gms carbohydrate with protein:
 2 TBSP jelly or sugar OR
 6 glucose tablets OR * ½ sandwich OR
 2 tubes Dextrose Gel * 3 graham crackers with one TBSP pea-

nut butter

Notify provider responsible for glucose management
ASAP and certainly PRIOR to administering the next
insulin or oral diabetes agent for medication and glucose
monitoring orders

GCDC 2017

Cardio Diabetes Medicine 2017 275

BG 45-59 mg/dL and Patient Conscious, Cooperative, and Able to Swallow

Immediate Action/Treatment Repeat Follow-up Treatment

*Staff to remain with patient Repeat BG and re-treat  If more than 1 hr until next meal/snack,
also give 15 gms of carbohydrate*:
DO NOT WAIT FOR LAB CONFIR- q15 min until BG > 70
MATION OF BG BEFORE TREAT-
ING mg/dL without symp- * 3 graham crackers OR * 6 saltine
toms or BG > 80 mg/dL. crackers OR * 8 oz skim milk.

Give 20 Grams Carbohydrate: Add order to check BG  If more than 2 hrs until next meal/snack.
 6 oz juice or regular pop OR at 0200 one time also add protein:
 1 ½ TBSP of jelly or sugar OR
 4 glucose tablets OR 1/2 sandwich OR
 1 ½ tubes Dextrose Gel 3 graham crackers with one TBSP peanut
butter

Notify provider responsible for glucose management
ASAP and certainly PRIOR to administering the next
insulin or oral diabetes agent for medication and glucose
monitoring orders

BG 60-100 mg/dL and patient Symptomatic and is Conscious, Cooperative and Able to Swallow

Immediate Action/Treatment Repeat Follow-up Treatment

Give 15 Grams carbohydrate: Repeat BG and re-treat q15 If more than 1 hr until next meal/snack,
• 4 oz juice or regular pop OR min also give 15 gms of carbohydrate*:
• 1 TBSP jelly or sugar OR until BG > 100 OR symptoms • 3 graham crackers OR
• 3 glucose tablets OR resolved • 6 saltine crackers OR
• 1 tube Dextrose Gel • 8 oz skim milk
Add order to check BG at If more than 2 hrs until next meal/snack.
0200 one time also add protein: 1/2 sandwich OR
3 graham crackers with one TBSP peanut
butter
Notify provider responsible for glucose
management ASAP and certainly PRIOR
to administering the next insulin or oral
diabetes agent for medication and glucose
monitoring orders

BG 60-70 mg/dLand patient has NO symptoms and Conscious, Cooperative and Able to Swallow

Immediate Action/Treatment Repeat Follow-up Treatment

No treatment required if scheduled Repeat BG and re-treat q15 If more than 1 hr until next meal/snack,
mealtime is within 30 min and patient min until BG > 100 OR symp- also give 15 gms of carbohydrate*:
willing/able to eat. toms *3 graham crackers OR
If mealtime is more than 30 min , give resolved *6 saltine crackers OR
15 Grams carbohydrate: *8 oz skim milk
4 oz juice or regular pop OR Add order to check BG at
1 TBSP jelly or sugar OR 0200 one time If more than 2 hrs until next meal/snack.
3 glucose tablets OR also add protein:
1 tube Dextrose Gel • sandwich OR

• 3 graham crackers with one TBSP peanut
butter

Notify provider responsible for glucose manage-
ment ASAP and certainly PRIOR to administering
the next insulin or oral diabetes agent for medi-
cation and glucose monitoring orders

Cardio Diabetes Medicine

276 Hypoglycemia How Critical it is?

BG 60-70 mg/dLand patient has NO symptoms and Conscious, Cooperative and Able to Swallow

Immediate Action/Treatment Repeat Follow-up Treatment

No treatment required if scheduled Repeat BG and re-treat q15 If more than 1 hr until next meal/snack,
also give 15 gms of carbohydrate*:
mealtime is within 30 min and patient min until BG > 100 OR symp- • 3 graham crackers OR
• 6 saltine crackers OR
willing/able to eat. toms resolved • 8 oz skim milk
• If more than 2 hrs until next meal/
If mealtime is more than 30 min , give Add order to check BG at
15 Grams carbohydrate: 0200 one time snack.
• 4 oz juice or regular pop OR also add protein:
• 1 TBSP jelly or sugar OR 1/2 sandwich OR
• 3 glucose tablets OR 3 graham crackers with one TBSP peanut
• 1 tube Dextrose Gel butter

BG 70 mg/dLand patient has NO symptoms NO TREATMENT REQUIRED

discontinuation of oral agents in the absence of an Practice Points
alternate method for diabetes control. These patients
should instead be converted to a subcutaneous or IV The relationship between glycemic control and mor-
insulin regimen during hospitalization. Management tality demonstrates a U- shaped or J –shaped curve
with insulin in these circumstances is safer and has with increased risk of death at both extremes.
the added benefit of increased dosing flexibility when
caloric intake is erratic.2 The association between hypoglycemia and mortality
may be more specific to ‘spontaneous hypoglycemia’
4.Glucose Monitoring as opposed to iatrogenic hypoglycemia, implying that
hypoglycemia may be a biomarker for poor progno-
Bedside monitoring of capillary blood glucose should sis rather than atrue cause of mortality.
be performed at least four times daily (i.e., before
meals and at bedtime for patients who are eating). Current guidelines for inpatient glycemic control
A glucose check at 3:00 a.m. can also be useful in recommend maintaining blood glucose values in
patients with fasting hyperglycemia1. An elevated the range of 140-180mg/dl(7.8-10mmol/l) for most
glucose level at that time could indicate insufficient patients. Values <100mg/dl(5.6mmol/l) should be
nighttime insulin dosing, whereas a low glucose level avoided, and therapy needs to be revised when val-
at that time may indicate an early peak in evening ues are<70mg/dl(3.9mmol/l)
insulin or insufficient caloric intake at bedtime.
Hypoglycemia unawareness is common particularly
5.Medical Nutrition therapy in ill and elderly hospitalized patients, often having
low glucose levels without symptoms. For pragmatic
A consistent carbohydrate diet is important to appro- reasons treatment is necessary when glucose levels
priately match the insulin regimen or secretagogue are<70mg/dl(3.9mmol/l) with or with out symptoms.
activity to food for optimum glucose control and
prevention of hypoglycemia3. All three meals should Less intensive control is appropriate for very ill or el-
follow a consistent carbohydrate approach that em- derly patients, while more intensive control may be
phasizes the importance of a mixed meal. appropriate for healthy, stable inpatients.

6.Applying Systems Risk factors for hypoglycemia include aggressive gly-
cemic control, older age, recent hospitalization, ter-
The recent ADA technical review1 discussed the use minal illness, number of comorbidities, renal failure,
of protocols or standardized order sets for sched- shock, mechanical ventilation, malignancy, hypoal-
uled and correction-dose insulin, which reduces re- buminemia and antecedent episodes of hypoglyce-
liance on sliding scale management for maintaining mia.
glucose control in the hospital.A team or multidis-
ciplinary approach is needed to establish hospital
pathways and implement intravenous infusion of
insulin for the majority of patients having prolonged
NPO status outside of critical care units.

GCDC 2017

Cardio Diabetes Medicine 2017 277

Conclusion

The diagnosis of hypoglycemia in critically ill patients
appears to be a challenge. Bedside glucose analyzers
are often not reliable at the low ranges of glycemia,
and hypoglycemia-related neurological signs may be
masked.

Whether spontaneous or linked with insulin infusion,
the occurrence of hypoglycemia in critical illness,
especially severe hypoglycemia, is associated with
a poor prognosis without clear identification of the
reason for this higher mortality.

Not surprisingly, intensive insulin strategy aiming to
achieve “normoglycemia” is accompanied by an in-
creased incidence of severe hypoglycemia. Because
of its potentially harmful and life-threatening con-
sequences, hypoglycemia represents the main limit
to the development of a tight blood glucose control
strategy in critical illness.

References:

1. Raphael D Hulkower,1Rena M Pollack,2 and Joel Zonszein*,2 Understand-
ing hypoglycemia in hospitalized patients Diabetes Manag (Lond). 2014
Mar; 4(2): 165–176.

2. Hypoglycemia and Risk of Death in Critically Ill PatientsThe NICE-SUGAR
Study InvestigatorsN Engl J Med 2012; 367:1108-1118

3. David W. Bates, MD, MSc.Unexpected Hypoglycemia in a Critically Ill
Patient. Annals of Internal Medicine 16 July 2002:Vol 137,N 2;110-117

4. Jean-Claude Lacherade, M.D.,1Sophie Jacqueminet, M.D.,2 and Jean-
Charles Preiser, M.D., Ph.D.An Overview of Hypoglycemia in the Criti-
cally IllJ Diabetes Sci Technol. 2009 Nov; 3(6): 1242–1249.

5. Moritoki Egi, MD, Rinaldo Bellomo, MD, Edward Stachowski, MD et
al.Hypoglycemia and Outcome in Critically Ill PatientsMayo Clin Proc.
2010 Mar; 85(3): 217–224.

Cardio Diabetes Medicine