Effect of Hydroxy Ethyl Starch on Blood Sugar Level In Comparison To
Ringer Lactate -A Randomized Controlled Clinical Study
Jitendra Agrawal1*, Rakhi Mittal2 and Arvind Kumar3 1,2Department of Anaesthesiology, G.R. Medical College Gwalior, MP, India
3Anesthesia Consultant, Gurgaon, India
Received date: April 02, 2018; Accepted date: May 05, 2018; Published date:
May 15, 2018.
*Corresponding author: Dr. Jitendra Agrawal, Associate Professor, Department
of Anaesthesiology, G.R. Medical College Gwalior474009, MP, India, E-mail:
Background: In a randomized, double blind, prospective study, we have evaluated the blood sugar level after one load of hetastarch(450/0.7)and ringer lactate in patients posted for surgeries under spinal anaesthesia.
Aim: A comparative evaluation of Blood sugar level after administration of Hydroxy Ethyl Starch and Ringer Lactate.
Method: After approval from institutional ethical committeefifty patients of age group 20 to 70 yrs of either sex scheduled for lower
abdominal and lower limb surgeries of more than 1 hr. under spinal anaesthesia were included in the studyafter informed written consent.
Group I received Lactated Ringer (RL) 500 ml as preloading and Group II patients received Hydroxyethyl Starch solution 6% 500 ml as
preloading.Blood sugar readings were taken at 30 min. intervals from basal reading for first 2 hours followed by one hourly reading for next
Results: Maximal blood glucose level in group I increased from basal value of 63.02 + 1.24 to 74.56 + 2.29 mg % at end of 2 hours which
was not statistically significant. In group II at end of 3 hours blood glucose level increased from basal value of 64.12 + 1.56 to 99.4 + 2.50 mg
% which was statistically significant (p< 0.05).
Conclusion: There was statistically significant increase in blood sugar values transiently in group II i.e. Hydroxy ethyl Starch group which
was within physiological limits and not sustained to cause serious concern in healthy individuals.
Keywords: Blood sugar level; HES; Ringer lactate; Spinal Anaesthesia;
Hyperglycemia is an undesirable but common occurrence in the
perioperative period. Of the many possible adverse effects of hyperglycemia
perhaps the most disturbing is the potential for hyperglycemia to worsen
neurological outcome after a period of cerebral ischemia. Thus, in
procedures in which intraoperative and perioperative cerebral ischemia
is likely (e.g. during elective circulatory arrest for repair of complex
cerebrovascular or cardiac disorders or during carotid end arterectomy,
shock due to trauma or perioperative bleeding), it is desirable to treat
preexisting hyperglycemia and prevent new onset of hyperglycemia.
The management of hyperglycemia may include a variety of techniques,
including the use of insulin, alteration in the dose of gluconeogenesis
enhancing drugs (e.g. glucocorticoids), and the reduction or deletion
of exogenous sources of parenteral glucose. The introduction of
artificial colloids has heralded a new alternative for volume expansion.
Hydroxyethyl starch solutions are frequently used for volume expansion
in preloading prior to spinal anaesthesia and also in other critically ill
patients for treatment of shock caused by hemorrhage, burns, surgeries,
or other trauma [1,2].
These Hydroxyethyl starch or glucose polymers are metabolized by
serum amylase to produce smaller molecules of starch polymers and free
glucose. Thus Hydroxyethyl starch solutions have potential to induce or
potentiate hyperglycemia especially when given to patients who have
diminished ability to metabolize exogenous glucose, e.g. patients with
The incidence of Diabetes Mellitus has increased worldwide and
further many patients are at risk as diagnosed by oral Glucose Tolerance
Test. They have impaired glucose tolerance 3 to 4 times more in incidence
in comparison to Diabetes Mellitus. The stress response due to surgery,
anxiety and even Vene-puncture leads to epinephrine release which leads
to adverse response like hyperglycemia, hypertension, tachycardia and
increased catabolism.Hyperglycemia can be detrimental to wellbeing of
the patient [3,4]. Hyperglycemia can damage many organs like brain,
kidneys, heart, spinal cord and others by causing ischemia. It blights the
White Blood Cells function and impairs wound healing.
Central Neural Blockade before surgical incision significantly reduces
or abolishes the stress response to surgery, particularly in pelvic and
lower limb surgeries. So, by considering all these factors, ill effects of
hyperglycemia in perioperative period and frequent use of colloids
(Hydroxyethyl Starch) as plasma expander, the present study aimed at
examining the effects of 6% Hetastarch 450 and Ringer Lactate on Blood
Glucose Levels in non diabetic patients undergoing surgical procedures
under Sub Arachnoid Block (SAB).
Preloading with Crystalloid: Crystalloid like Ringer lactate and normal
saline has been used extensively for preloading.
Problems of preloading with Crystalloids:
• It has short intravascular half life. About 75-80% of this solution leaks
rapidly (15-20 mins) into the interstitial space. Thus, they do not expand
the volume in real sense and large volume of crystalloid is required.
Large fluid volume may decrease O2 carrying capacity or increase the
risk of pulmonary oedema in susceptible patients.
• Large volume of infusion (20 ml/kg) may itself cause hypotension by
stimulating secretion of ANH (Atrial Natriuretic Peptide Hormone) due
to right atrial stretching which has direct relaxing action on vascular
Such crystalloid preloading may bring down the incidence of
hypotension from 80% to 43-65%. The era of crystalloid preloading has
ended due to these problems.
Preloading with Colloids: Colloids are mainly confined to the
intravascular space because of their high oncotic pressure that will move
fluid from the interstitial space into intravascular space resulting in
augmentation of the intravascular volume by a factor that is greater than
the volume of colloid infused. Such colloid solutions are called plasma
expanders and need to be distinguished from plasma volume substitute
that do not expand the intravascular volume.
Other advantages of colloids are-
• Maintain arterial pressure, CVP and other cardiovascular parameters
for longer time (2-4 hour) due to long IV half life.
• Lower volumes of fluid are required for preloading, thus minimal risk of
overloading of cardiovascular system.
• Minimizes the use of vasoconstrictor drugs.
Materials and Methods
This study was carried out in the Department of Anaesthesiology,
Gandhi Medical College and associated Hamidia and Sultaniazanana
hospital Bhopalafterapproval from institutional ethical committee.The
study comprised of 50 cases of American Society of Anesthesiologists
physical status I and II were required in the study and were randomly
assigned¬ into two groups of 25 each depending upon the intravenous
fluid Hydroxyethyl Starch or Lactated ringer used for preloading before
central neuraxial blockade.All the patients were carefully screened in the
preanesthetic check-up room.
A meticulous attention was paid in excluding all the patients with
systemic disorders like Diabetes Mellitus, Congestive Heart Failure
& Chronic Renal Failure. Patients on drugs such as Glucocorticoids,
Phenytoin, Oral Contraceptives, Furosemide, and Niacin etc. were also
excluded from the study. Preloading was done 15 minutes before SAB.
Heart rate (ECG), Non-invasive Blood pressure, Pulse oximetry, respiratory
rate, and basal blood sugar value were recorded and monitored. Blood
sugar values were taken 30, 60, 90,120, 180, 240, 300, 360 minutes after the
Subarachnoid Blockby accucheck glucometer. All vital parameters were
monitored carefully and the occurrence of any side effects was also looked
after. The results were analyzed statistically.
After preloading with the assigned intravenous fluid the patient received
only Normal Saline as subsequent intravenous fluid till the final blood
sugar reading was taken at the end of six hours. Blood sugar readings were
taken at 30 min. intervals from basal reading for first 2 hours followed
by one hourly reading for next 4 hours (30, 60, 90,120,180,240,300,360
min. after infusion). All eight blood sugar values were recorded and the
differences in values were calculated.
Maximal blood glucose level in group I increased from basal value
of 63.02 + 1.24 to 74.56 + 2.29 mg % at end of 2 hours which was not
statistically significant. After this the blood sugar level gradually declines.
Similarly in group II at end of 3 hours blood glucose level increased from
basal value of 64.12 + 1.56 to 99.4 + 2.50 mg % which was statistically
significant (p< 0.05). After this the blood sugar level gradually declines.
The present study was carried out in 50 patients of ASA grade I and
II scheduled for lower abdominal and lower limb surgery under central
neuraxial blockade in the department of anaesthesiology at Gandhi
medical college and associated Hamidia and SultaniaZanana hospital
Bhopal.The following observations were recorded- [Tables: 1,2]
The above table records variations in pulse rate after neuraxial blockade
and crystalloid or colloid administration. There was no statistically
significant change in pulse rate. [Table: 3]
There were no significant changes in systolic blood pressure after
Subarachnoid Block and crystalloid or colloid administration.[Table: 4]
It can be seen that there was no significant change in mean respiratory
Table 1: Effects on Blood Sugar Levels
|Time (in min.)
||Avg. Rise in Blood sugar level in group I (RL) (in mg %)
||Avg. Rise in blood sugar level in group II (HES) (in mg %)
||62.01 + 1.77
||59.36 + 1.42
||66.49 + 1.56
||79.08 + 1.82*
||66.49 + 1.56
||88.24 + 1.64*
||74.568 + 2.29
||96.45 + 2.26*
||70.34 + 1.81
||99.40 + 2.50*
||68.85 + 1.56
||92.54 + 2.12*
||67.56 + 1.62
||90.36 + 1.92*
||67.32 + 1.58
||89.80 + 1.96*
Table 2: Effect on pulse rate
||Time of observations
||Group I (RL)
||Group II (HES)
Table 3: Effect on Systolic Blood Pressure
||Time of observations
||Group I (RL)
||Group II (HES)
Table 4: Effect on Respiratory Rate
||Time of observations
||Mean Resp. rate
Maximal blood glucose level in group I increased from basal value
of 63.02 + 1.24 to 74.56 + 2.29 mg % at end of 2 hours which was not
statistically significant. In group II at end of 3 hours blood glucose level
increased from basal value of 64.12 + 1.56 to 99.4 + 2.50 mg % which was
statistically significant (p< 0.05).
All the continuous variables were presented as the mean + SD. And
nonparametric data were reported as percentage. 95% confidence interval
(CI) was mentioned in different analysis. We performed chi square test,
which is used for testing hypothesis about nominal data. Survival analysis
was done by using Kalpan-meri curve. Statistical analysis was conducted
with IBM SPSS 17.0 for windows and Medcalc version 184.108.40.206. All the
comparisons were performed with 2-tailed P values. The results were
considered significant at P value < 0.05.
The exacerbation of hyperglycemia in known diabetics and the new
onset of hyperglycemia in previously non diabetics are well appreciated
occurrences in perioperative surgical patients. The increases in blood
glucose concentrations may be related to a variety of conditions, including
stress, corticosteroid use, anaesthetic agents, i.v. infusions of glucose, and
i.v. hyper alimentation other than glucose.
In hyperglycemic patients, increases in blood glucose concentrations,
per se, are credited with the initiation of a number of conditions that may
adversely affect patients. The increased osmotic load introduced by glucose
may result in an osmotic diuresis, making it difficult to assess intravascular
volume status by measuring hourly urine output. Hyperglycemia may
inhibit wound healing and, because of an inhibition of white blood cell
activity, may inhibit the ability to fight infections.Although a variety of
techniques may be used to acutely decrease blood glucose values in the
perioperative period, one option is to delete hyperglycemia-inducing
drugs and solutions from the patient’s therapy, particularly during
periods in which the patient is at greatest risk for an adverse effect from
The present study entitled “Blood sugar level after the administration of
Hydroxyethyl Starch – comparison of one volume load of Hetastarch and
Ringer Lactate “was carried out in the Department of Anaesthesiology,
Gandhi Medical College and associated Hamidia & Sultania Zanana
Hospital Bhopal after approval from institutional ethical committee.
As stress and pain causes release of catecholamines which lead to rise
in blood sugar level as occur due to fluctuation in depth of anaesthesia.
Our study has been carried out in 50 patients of ASA grade I and II who
were scheduled for lower limb or lower abdominal surgery under central
neuraxial blockade as SAB or Epidural causes little or no stress response
in these surgeries.Subarachnoid block or epidural causes sympathetic
blockade resulting in hypotension. We have used ringer lactate and
Hydroxyethyl starch as preloading fluid before the block was given.
McClain CD, McManus ML et al studied that fluid and electrolyte
disturbances are common among children and fluid management is
critical to the successful care of a wide range of pediatric conditions. The
chapter outlined the basic anatomy and physiology of fluid compartments,
their developmental maturation, and a general approach to fluid
administration. Clinical assessment of hydration states, perioperative
fluid management, and the care of common pathophysiologic states are
discussed in detail. Specific attention is given to acid–base balance and to
disorders of sodium, potassium, and water homeostasis .
YACOBI A, STOLL RG et al. on the other hand told about
pharmacokinetics of hydroxyethyl starch in normal subjects. Ten
volunteers were given 500 ml 6% HES solution by intravenous infusion,
and serial blood and urine samples were collected for nonglucose total
carbohydrate determination. As expected, the infusion of HES resulted in
plasma volume expansion over a 48‐hour period during which time levels
of nonglucose carbohydrates were above 3.5 mg/ml. HES is metabolized
by α‐amylase in the body. During the first 48 hours after infusion of
HES, plasma α‐amylase activity was significantly increased over control.
Concomitantly, α‐amylase activity in urine was also elevated but not
significantly so .
In another similar study, Jungheinrich C, Neff TA et al found that
hydroxyethyl starch has recently become the subject of renewed interest
because of the introduction of a new specification, hydroxyethyl starch
130/0.4, as well as the clinical availability of a solution using a previous
hydroxyethyl starch type (hydroxyethyl starch 670/0.75) with a carrier
other than 0.9% saline.Various types of hydroxyethyl starch show different
pharmacokinetic behaviour. Since hydroxyethyl starch is a polydisperse
solution acting as a colloid, pharmacodynamic action depends on the
number of oncotically active molecules, not on the plasma concentration
alone; the pharmacodynamics with respect to the volume effect does
not directly mirror pharmacokinetics in the case of hydroxyethyl starch
solutions. Equivalent volume efficacy has been proven for hydroxyethyl
starch 130/0.4 compared with 200/0.5. Prolonged persistence of
hydroxyethyl starch in plasma and tissues can be avoided by using rapidly
metabolisablehydroxyethyl starch types with molar substitution < 0.5.
Influence on coagulation is minimal with hydroxyethyl starch 130/0.4,
and no adverse effects on kidney function have been observed even with
large repetitive doses when used according to the product information .
Klotz U, Kroemer H. et al studied clinical pharmacokinetic
considerations in the use of plasma expanders. This review deals with the
pharmacokinetics of dextrans and hydroxyethylstarch, the most commonly
used plasma expanders. The complex composition of these colloidal
agents (broad range of molecular weight distribution in vitro and in vivo,
) confounds their specific assay and meaningful pharmacokinetic analysis.
Extrarenal excretion and metabolism of dextrans by dextranases account
for only 2 to 10% of the overall drug loss from the body. Dextran species
with a molecular weight below 15,000 daltons are filtered unrestricted,
and consequently the elimination half-life of dextran 1 is relatively short
(2 hours) and that of dextran 40 (10 hours) or dextran 60 (42 hours) much
longer. In conclusion, the disposition and pharmacological effects of
plasma expanders are related to time-dependent changes in the molecular
weight distribution of the plasma concentration decline. Unfortunately,
the analytical assays applied in most studies were not able to differentiate
the complex mixture of the infused colloids .
Murty SS, Kammath S et al did a randomized double blind study on
the effects of hydroxyethyl starches on blood sugar levels. Hofer RE,
Lanier WL et al in a similar study saw effect of hydroxyethyl starch
solutions on blood glucose concentrations in diabetic and nondiabetic
rats. The effects of i.v. infusions of 6% hetastarch or 10% pentastarch
on blood glucose concentrations were tested. Neither hetastarch nor
pentastarch infusions significantly altered blood glucose values over
the 3-hr study period, regardless of whether the rats were diabetic or
nondiabetic. Assuming these data are transferable to humans, the authors
conclude that hydroxyethyl starch solutions do not produce or exacerbate
hyperglycemia, and furthermore, that their use is not contraindicated in
subjects having hyperglycemia from diabetes mellitus or iatrogenic causes
Cullingford DW etal studied the blood sugar response to anaesthesia
and surgery in southern Indians During the course of anaesthesia and
surgery in South India, it was noticed that Indian and European patients
responded differently. In an attempt to evaluate these differences, blood
sugar values were used as a guide to the sympathetic nervous response.
Under general anaesthesia values rose and stayed higher in Indian
patients than in Europeans in India or England. General anaesthesia by
itself provoked no elevation until the commencement of surgical trauma.
Under subarachnoid or epidural analgesia, no major change in blood sugar
occurred during surgery. During the study involving 141 patients, three
collapsed unexpectedly and resuscitative measures invalidated the blood
sugar results. Although nutrition might play some part, the differences are
considered to be racial and not climatic .
Hydroxyethyl Starch (HES), a commonly used resuscitation fluid, has
the property to induce hyperglycemia as it contains large ethyl starch,
which can be metabolized to produce glucose. Jung KT, Shim SB et al
studied effect of hydroxyethyl starch on blood glucose levels.in nondiabetic
patients undergoing elective lower limb surgery under spinal
anesthesia.Fifty-eight patients were divided into two groups according
to the type of the main intravascular fluid used before spinal anesthesia
(Group LR: lactated Ringer’s solution, n = 30 vs. Group HES: 6%
hydroxyethyl starch 130/0.4, n = 28). Blood glucose levels were measured
at the following time points: 0 (baseline), 20 min (T1), 1 h (T2), 2 h (T3), 4
h (T4), and 6 h (T5). Mean blood glucose levels at T5 in the LR group and
at T4, T5 in the HES group, increased significantly compared to baseline.
There were no significant changes in the serial differences of mean blood
glucose levels from baseline between the two groups. Administration of
6% HES-130 increased blood glucose levels within the physiologic limits,
but the degree of glucose increase was not greater than that caused by
administration of lactated Ringer’s solution. In conclusion, the authors
did not find evidence that 6% HES-130 induces hyperglycemia in nondiabetic
In another similar study, which also corelates well with our study, Patki
A, Shelgaonkar VC et al. studied effect of 6% hydroxyethyl starch-450
and low molecular weight dextran on blood sugar levels during surgery
under subarachnoid block.The following study was designed to compare
6% hydroxyethyl starch-450 with Dextran 40, both used as preloading
fluids, for their potential to raise peri-operative blood glucose levels.
All the three preloading fluids, were seen to significantly increase the
capillary blood glucose levels intra-operatively (P < 0.05), but the rise with
Dextran-40 was seen to be sustained and highly significant (P < 0.001).
We thus conclude that, Dextran40 causes a sustained and significant rise
in peri-operative blood glucose levels .
Li Y, He R, Ying X, Hahn RG. Ringer’s lactate, but not hydroxyethyl
starch, prolongs the food intolerance time after major abdominal surgery.
The infusion of large amounts of Ringer’s lactate prolongs the functional
gastrointestinal recovery time and increases the number of complications
after open abdominal surgery. The order of the infusions had no impact on
the outcome. Both the administration of ≥ 2 L of Ringer’s lactate and the
development of a surgical complication were associated with a longer time
period of paralytic ileus and food intolerance (two-way ANOVA, P < 0.02),
but only surgical complications prolonged the length of hospital stay
(P < 0.001). The independent effect of Ringer’s lactate and complications
of food intolerance time amounted to 2 days each. The infusion of ≥ 1 L
of hydroxyethyl starch did not adversely affect gastrointestinal recovery.
To conclude, Ringer’s lactate, but not hydroxyethyl starch, prolonged the
gastrointestinal recovery time in patients undergoing laparoscopic cancer
Wilkes NJ, Woolf R et al. studied the effects of balanced versus salinebased
hetastarch and crystalloid solutions on acid-base and electrolyte
status and gastric mucosal perfusion in elderly surgicalpatients. Fortyseven
elderly patients undergoing major surgery were randomly allocated
to one of two study groups. Patients in the Balanced Fluid group received
an intraoperative fluid regimen that consisted of Hartmann’s solution and
6% hetastarch in balanced electrolyte and glucose injection (Hextend).
Patients in the Saline group were given 0.9% sodium chloride solution and
6% hetastarch in 0.9% sodium chloride solution (Hespan®). Biochemical
indices and acid-base balance were determined. Gastric tonometry was
used as a reflection of splanchnic perfusion. Postoperative chloride levels
demonstrated a larger increase in the Saline group than the Balanced Fluid
group. In this study, the use of balanced crystalloid and colloid solutions
in elderly surgical patients prevented the development of hyperchloremic
metabolic acidosis and resulted in improved gastric mucosal perfusion
when compared with saline-based solutions .
The consequences of hyperglycemia are disastrous for patients like
bad neurological outcome, damage to kidney, heart, and other organs
by causing ischemia, also impairs white blood cells function and wound
healing.Thus there was statistically significant increase in blood sugar
values transiently in group II which was within physiological limits and
not sustained to cause serious concern in healthy individuals.
Baraka AS, Ghabach T. Intravenous administration of polymerized gelatin versus isotonic saline for prevention of spinal induced hypotension. Anaesthanalg. 1997;84:106-110.
Koski E, Tuppuranien T, Mattila M, Gordin A, Salo H: Hydroxyethyl starch, Dextran-70 and balanced salt solution in correction of hypotension during epidural anaesthesia. Acta Anaesthesiologica Scand. 1984;28(6):595-599.
Cullingford DW. The blood sugar response to anaesthesia and surgery in southern Indians. British journal of anaesthesia. 1966;38(6):463-470.
Cook R, Malmqvist LA, Bengtsson M, Tryggvason B, Lofstrom JB. Vagal and sympathetic activity during spinal analgesia. Acta Anaesthesiol Scand. 1990;34(4):271-275.
McClain CD, McManus ML. Fluid management. InA Practice of Anesthesia for Infants and Children (Sixth Edition) 2019:199-216.
Yacobi A, Stoll RG, Sum CY, Lai CM, Gupta SD, Hulse JD. Pharmacokinetics of hydroxyethyl starch in normal subjects. The Journal of Clinical Pharmacology. 1982;22(4):206-212.
Jungheinrich C, Neff TA. Pharmacokinetics of hydroxyethyl starch. Clinical pharmacokinetics. 2005;44(7):681-699. doi: 10.2165/00003088-200544070-00002
Klotz U, Kroemer H. Clinical pharmacokinetic considerations in the use of plasma expanders. Clinical pharmacokinetics. 1987;12(2):123-135. doi: 10.2165/00003088-198712020-00003
Murty SS, Kammath S, Chaudhari LS. Effects of hydroxyethyl starches on blood sugar levels: a randomized double blind study. Indian J Anaesth. 2004;48:196-200.
Hofer RE, Lanier WL. Effect of hydroxyethyl starch solutions on blood glucose concentrations in diabetic and nondiabetic rats. Critical care medicine. 1992;20(2):211-215.
Jung KT, Shim SB, Choi WY, An TH. Effect of hydroxyethyl starch on blood glucose levels. Korean journal of anesthesiology. 2016;69(4):350-356. doi: 10.4097/kjae.2016.69.4.350
Patki A, Shelgaonkar VC. Effect of 6% hydroxyethyl starch-450 and low molecular weight dextran on blood sugar levels during surgery under subarachnoid block: A prospective randomised study. Indian journal of anaesthesia. 2010;54(5):448-452. doi: 10.4103/0019-5049.71045
Li Y, He R, Ying X, Hahn RG. Ringer’s lactate, but not hydroxyethyl starch, prolongs the food intolerance time after major abdominal surgery; an open-labelled clinical trial. BMC Anesthesiology. 2015;15(1):72. doi: 10.1186/s12871-015-0053-5
Wilkes NJ, Woolf R, Mutch M, Mallett SV, Peachey T, Stephens R, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesthesia & Analgesia. 2001;93(4):811-816.