Hemraj Tungria¹, A P Verma², Mamta Khandelwal³, Devendra Verma^4*

 

¹Associate Professor, ⁴Sr. Professor Department of Anesthesiology, RNT Medical College Udaipur, Rajasthan, INDIA.

²Senior professor, ³Associate Professor, Department of Anesthesiology, SMS Medical College and Zenana Hospital, Jaipur Rajasthan, INDIA.

Email: htungaria@gmail.com, anandaverma@yahoo.com, drmamtakhandelwal@gmail.com, devendra.anaes@yahoo.in

In group 1, maximal blood sugar level increased from basal value of 94.57±12.69 mg/dl to 112.63±20.07mg/dl at the end of twelve hours (an increase of 18.07±15.26mg/dl; P value <0.001) which was statistically highly significant. In group 2, the blood sugar level increased from the basal value of 87.93±10.26 mg/dl to 125.50±9.79 mg/dl at the end of 12 hours (an increase of 37.57±9.73 mg/dl; P value <0.001). In group 3, maximal blood sugar level was observed at 12 hours (119.37±17.15mg/dl; P value <0.001) which was similar to group 1and2. In group 4 there was a significant increase in BSL from basal value 7^th hour onward. The maximal blood sugar level was observed at 12 hours (122.63±19.43mg/dl; ↑26.33±19.64mg/dl i.e. 27.35% from basal value; P value <0.001) which was similar to group 1, 2and 3. Similarly in group 5, maximal blood sugar level was observed at 12 hours (120.37±18.17mg/dl; an increase of 26.20±15.05mg/dl i.e. 27.82% from basal value; P value <0.001) which was similar to group 1, 2, 3 and 4.

 

Table 2: Mean change in blood sugar level (± S.D.) in mg/dl from the baseline (0hrs)

Observation time (Hrs)	Group 1 (RL)		Group-2 (6%HES450/0.7)		Group-3 (6%HES200/0.5)		Group-4 (3%HES200/0.5)		Group-5 (6%HES130/0.4)
	Mean change± S.D.(% variation)	P value (sig.)	Mean change ± S.D. (% variation)	P value (sig.)	Mean change ± S.D.(% variation)	P value (sig.)	Mean change ± S.D.(% variation)	P value (sig.)	Mean change ± S.D.(% variation)	P value (sig.)
1	-3.37±8.56 [-3.56%]	0.0398	0.47±9.64 [0.53%]	0.7927	-0.73±11.50 [-0.77%]	0.7294	-4.00±12.17 [-4.15%]	0.0823	0.73±11.99 [0.78%]	0.7399
3	4.27±13.99 [4.51%]	0.1055	7.97±9.18 [9.06%]	0.0001	1.57±14.50 [1.63%]	0.5585	2.10±14.85 [2.18%]	0.4449	7.80±12.95 [8.28%]	0.0026
5	6.47±13.47 [6.84%]	0.0135	13.27±9.22 [15.09%]	<0.001	10.90±18.12 [11.37%]	0.0026	4.47±14.44 [4.64%]	0.1009	15.77±12.95 [16.74%]	<0.001
7	11.10±11.70 [11.74%]	<0.001	23.30±11.15 [26.50%]	<0.001	22.50±24.40 [23.48%]	<0.001	19.17±21.24 [19.90%]	<0.001	22.83±14.56 [24.25%]	<0.001
12	18.07±15.26 [19.10%]	<0.001	37.57±9.73 [42.72%]	<0.001	23.53±17.01 [24.56%]	<0.001	26.33±19.64 [27.35%]	<0.001	26.20±15.05 [27.82%]	<0.001

Table 3: Mean serum sodium level (± S.D.) and minimum and maximum value in mEq/L at various time intervals in patient in different groups

Mean change in serum sodium level from basal value in all the groups ranged from -2.17±6.20mEq/L to 1.05±6.27mEq/L. In all the five groups none of the patients showed significant deviation in the serum sodium level from basal value.

 

 

Table 4: Mean change in serum sodium level (± S.D.) in mEq/L from the baseline (0hrs)

Table 5: Mean serum potassium level (± S.D.) and minimum and maximum value in mEq/L at various time intervals in patient in different groups

In all the groups there was a continuous and statistically significant decline in mean serum potassium level compared to basal value and serum potassium level remained below the basal value throughout the study period. Group 3 (6% Pentastarch 200) and group 5 (6% Tetrastarch 130) exhibited the maximum fall in serum potassium level from 7^th hour onwards. Out of all five groups, group 4 (3% Pentastarch) exhibited the least deviation in serum potassium level and this was the reason, when the group 4 was compared with other groups the comparison was highly significant.

Table 6: Mean change in serum potassium level (± S.D.) in mEq/L from the baseline (0hrs)

Table 7: Mean serum chloride level (± S.D.) and minimum and maximum value in mEq/L at various time intervals in patient in different group

In group 1, 3 and 4 there was statistically no significant change in Mean serum chloride level from baseline value throughout the study period. In group 2 there was statistically significant (P value <0.05) decrease (0.96%) in Mean serum chloride level at 12 hours from baseline value. Mean serum chloride level varied in the range of -2.10 to-0.93 mEq/L from baseline value. This difference was clinically and statistically not significant most of the time

Table 8: Mean change in serum chloride level (± S.D.) in mEq/L from the baseline (0hrs)

Table 9: Mean serum calcium level (± S.D.) and minimum and maximum value in mg% at various time intervals in patient in different groups

In all the groups there was continuous decline in Mean serum calcium level from basal value throughout the study period. The comparison of group 4 with groups 2, 3 and 5 was statistically highly significant since the deviation in the concentration of serum calcium was least in group 4 throughout study period i.e. at 1,3 5,7,12 hrs but the maximum decrease was found in Hetastarch group (6% HES-450) to the extent of 7.85% and least in tetrastarch group (6% HES-130) i.e. 3.62% at 12 hrs.

Table 10: Mean change in serum calcium level (± S.D.) in mg% from the baseline (0hrs)

DISCUSSION

The artificial colloid Hydroxyethylstarch (HES) is available in different types according to their concentration, molecular weight, degree of substitution,C2/C6 ratio, source of starch (waxy maize derived or potato starch derived) and their carrier solution (normal saline or balanced salt solution). The older HES products were associated with adverse effects like pruritus, coagulopathy, platelet dysfunction, elevated serum amylase level, hemodilution, renal dysfunction, hyperbilirubinemia, hearing loss, tissue accumulation etc. So they evolved over time retaining their volume efficacy with improved safety and pharmacological profile. Reduction in molecular weight and degree of substitution led us to newer third generation HES with shorter half life, improved pharmacokinetic and pharmacodynamics properties and lesser side effect^1,2. Hydroxyethyl starch was introduced in 1957 and the first generation Hetastarch was introduced into clinical practice during the 1970s. Older HES were semisynthetic colloid produced by hydroxyethyl substitution of amylopectin, a D-glucose polymer obtained from sorghum or maize. So this conformationally different polysaccharide is difficult to be metabolized by serum amylases. This leads to increase in half life of the HES and is more prominent when the hydroxyethyl residue is bound to C2 or C6 position of glucose. But they were associated with many adverse effects^1,2. Various molecular modifications during the 1980s and 1990s leave us with the second generation Pentastarches and subsequently third generation low molecular weight tetra starches in common use today. They differ in their mean molecular weight (MW), molar substitution (MS) and C2/C6 ratio, source of starch, and carrier solution. These above modifications were mainly done to increase in half life along with to decrease incidences of adverse effects^1,2. HES are identified by three numbers, for eg. 6% HES 450/0.7, 3% HES 200/0.5 etc. the first number denotes the concentration of the solution, the second represents the mean molecular weight in kiloDalton (kDa) and the third one is Molar substitution. These three indicators are highly relavant to the pharmacokinetic of the HES^1,2.

Concentration: it mainly reflects initial volume effect ie 6% HES solutions are isooncotic with blood, means one litre HES replaces one litre of blood loss.10% HES are hyperoncotic having volume effect more than the volume infused(about 145%)

Molecular weight: may be high (>400kD), medium (200-400 kD), and low (<200 kD) molecular weight solution.

Molar substitution: defined as mole hydroxyethyl residue per mole glucose subunit. They may be highly (0.62-0.75;hetastarch), medium (0.5; pentastarch), low substituted solution (0.4; tetrastarch)

C2/C6 ratio: solution with high (>8) and low (<8) C2/C6 ratio. After an IV infusion smaller HES molecules (less than renal threshold ie 45-60 kDa) are excreted and bigger molecules are enzymatically metabolized into smaller molecules until the renal threshold for excretion is reached. HES with low Molecular Substitution are broken down more rapidly to produce greater concentration of oncotically active particles. Part of HES diffuses into interstitial space, redistributed and ultimately eliminated and other is taken up by the reticuloendothelial system and broken down slowly. Thus, the degree of plasma and tissue accumulation is highly dependent on structure, the specific HES type, and its physicochemical properties. HES with high molecular weight, C2/C6 ratio and degree of substitution are associated with more side effects^1,2. There are various studies evaluating HES and their volume expansion, pharmacodynamics and pharmacokinetic properties, effect on coagulation, acid base status, blood sugar level, platelet function etc. There is no such study comparing all saline based three generation HES and their effect on blood sugar level and serum electrolytes. So this study was planned with the aim to evaluate effect of different generation of saline based HES and balanced salt solution ringer lactateon blood sugar and serum electrolytes. We have taken 150 patients, 30 patients in each group.

Blood Sugar Level: There was a steady rise in the blood sugar level in all the groups and it did not return to basal value in any group even up to 12 hours. The highest increase (42.72%) in blood sugar level was in 6% HES-450 group. However this finding is valid only statistically since the basal value in this group was much lower in comparison to other groups. The values of mean blood sugar level were otherwise comparable to other groups throughout the study period. It was a surprising finding that in group 1 eleven patients had blood sugar level more than 131 mg/dl at 3hours. As far blood sugar level is concerned group 2 exhibited a fair compliance. Thus it is evident that the breaking of the HES molecule to glucose is delayed in hetastarch. Even control group had a statistically significant rise in blood sugar level. The increase in glucose level although statistically significant was thought not to be clinically relevant in all these patients. Ringer’s lactate has the potential to cause hyperglycemia due to conversion of lactate to glucose via the Cori’s cycle. In the diabetic patients, peripheral disposal of lactate may be impaired because of inactivation of pyruvate dehydrogenase, while gluconeogenesis will be enhanced simultaneously. Thus in diabetic patients, lactate will be converted to glucose causing marked hyperglycemia although this does not hold true in non-diabetics to the same extent. In the non diabetics also, an increase in blood sugar level was found. Murty et.al¹³(2004) studied effects of 6% Hetastarch, 6% Pentastarch 200 and Ringers lactate as preloading fluids in spinal anaesthesia on blood sugar levels and concluded starches significantly increased blood sugar levels (p<0.05), with peak at the end of two hours with hetastarch and at the end of 3hours with Pentastarch, RL however did not increase blood sugar levels. While in our study rise in BSL was also in RL group. Abhiruchi Patki and VC Shelgaonkar⁸ (2010) concluded that Ringer’s lactate and Hydroxyethyl starch 6%-450 significantly raise the blood sugar level, albeit within physiological limits. So our study is in correlation with this study. A study done by D.J.B. Thomas and K.G.M.M. Alberti¹⁴ (1978) who used hartmann solution in diabetic and nondiabetic patients. The rise in blood sugar was more in diabetics as compared to nondiabetics. R. Beyer et al⁶ (1997) also found similar rise in BSL with the use of 6%HES 200. Ki Tae Jung et al¹⁰ (2016) and R. Raghu et al¹¹ (2015) also observed increase in BSL both in RL and 6% HES group but more in high molecular weight HES. In a study by Norbert H. Vogt et al⁵(1996) there was gradual decline in mean BSL at 1,3, 6 hrs postoperatively different from our study. It might be due to different type and duration of surgery (>2 hrs) with substantial blood loss and simultaneous replacement of the losses with PRBC, FFPs and platelets along with HES intraoperatively. Study by S.S.Nath et al⁹ (2015) with balanced 6% HES 130 shows no increase in BSL compared to Normal saline group. Results are different from our study, because they used 10 ml/kg tetrastarch as preloading which is less than our study. So from above studies it is concluded that higher molecular weight HES raises BSL significantly more as compared to low molecular weight HES. Ringer Lactate is associated with increased BSL than Normal Saline but to a lesser degree than HES.

Serum Sodium Level: There was no significant Mean change in serum sodium level from basal value in any group throughout the study period. The variation ranges from -2.17 to +1.05 mEq /L from basal value. A study done by Norbert H. Vogt et al⁵ (1996), R. Beyer et al⁶ (1997), G. B. Lehmann et al⁴ (2007) showed there were no change in the serum electrolytes (Na⁺, K⁺andCl^-) even after using 3000,2400,500 ml for 5 days respectively in the time course of study period. Our study results for serum sodium are similar to these studies. Nicholas J Wilkies et al¹⁵ (2001) and Subir K Brahma et al¹⁶ (2017) in their study with use of balanced versus saline based HES and crystalloid solution perioperatively found no significant changes in serum sodium level in both the group. So these result further supported our study. In our study we used saline based HES as preloading fluid and balanced salt solution RL as subsequent fluid for the entire study period. So it might be the cause for no significant changes in serum sodium level.

Serum Potassium Level: In all the study groups, serum potassium level remained below basal value throughout the study period. In fact no possible valid / justifiable explanation can be produced for the decline in potassium level in our study. Surprisingly even in control group there was a significant decrease in serum potassium level from baseline value at 1^st hour and the decrease became highly significant from 3^rd hour onward. Out of all five groups, group 4 exhibited the least deviation in serum potassium level and this was the reason, when the group 4 was compared with other groups the comparison was highly significant. It seems that 3% Pentastarch produces the least displacement of serum potassium; the comparison of this group with other groups made the statistical significance prominant. The mean values of serum potassium were within the physiologic range throughout the study period and the clinical progress throughout the surgical course remained uneventful. Bogumila Woloszczuk-Gebicka (2006)¹⁷supported our study while studies by Norbert H. Vogt et al⁵ (1996) R. Beyer et al⁶ (1997), G. B. Lehmann et al⁴ (2007), Nicholas J Wilkies¹⁵ (2001) et al and Subir K Brahma et al¹⁶(2017) have different results. It might be due to difference in volume of HES used, duration of the study period and use of arterial blood for sampling.

Serum Chloride Level: Mean serum chloride level varied in the range of -2.10 to-0.93 mEq/L from baseline value. In group 5 there was a statistically significant (P value <0.05) change in Mean serum chloride level from 3^rd hour onwards but the mean values were well within the physiological limits. Sodium chloride is often administered because it is isotonic with plasma and is initially distributed in the extracellular compartment. Non physiologic levels of chloride however have been linked to the development of metabolic acidosis and the possible impairment of splanchnic perfusion as judged by the abdominal discomfort and reduced urine output. Norbert H. Vogt et al⁵ (1996), and G. B. Lehmann et al⁴ (2007), supported our study while studies by Bogumila Woloszczuk-Gebicka¹⁷ (2006) and Nicholas J. Wilkes¹⁵ (2001) showed hyperchloridemia in their studies. Nicholas J Wilkies et al¹⁵ (2001)and Subir K Brahma et al¹⁶ (2017) in their study with use of balanced versus saline based HES and crystalloid solution perioperatively found significant changes in serum chloride level ie hyperchloridemia in saline based solution group. Use of balanced salt solution RL throughout study period after initial preloading with saline based HES might explain minimal variation in serum chloride level. Nicholas J Wilkies et al¹⁵ and Subir K Brahma¹⁶ also found significant variation in saline based groups rather than in balanced group. The comparison of group 2 with other groups was found statistically significant though the values in other groups were also well within the physiologic range.

Serum Calcium Level: In all the groups there was continuous and statistically significant (p value <0.05)decline in Mean serum calcium level from basal value throughout the study period. Group 2 and 3 exhibited the fall in a large number of patients. Once again, the tendency to cause a fall in serum calcium did not even spare the control group. R. Beyer et al⁶ (1997) compared HES and Gelatin in 48 patients of orthopedic surgery. serum calcium Values in the HES group remained significantly low for up to 12 hours (7.8±0.7mg%) after operation. At 24 hours postoperatively it was 8.1±0.4mg%. Our results also correlate very well with this study. Nicholas J Wilkies et al¹⁵ in their study with use of balanced versus saline based HES and crystalloid solution perioperatively found highly significant (p value 0.0001) decrease in serum calcium level in both the group. The decrease in total serum calcium in all the groups can be explained by the known “rule of thumb” whereby a decrease in albumin concentration of 1g/dl is accompanied by a decrease in total serum calcium of 0.8mg%. However, Studies by Vogt, Schönberger and Kilian¹⁸ have confirmed that HES does not specifically affect ionized calcium even at higher doses. The comparison of group 4 with groups 2, 3 and 5 was statistically highly significant since the deviation in the concentration of serum calcium was least in group 4. The effect of 3% HES 200/0.5 on plasma oncotic pressure, total plasma proteins and serum albumin requires further study to provide a further clue as to the fact that why it produces least deflection in serum calcium.

 

CONCLUSION

In our study, increase in blood sugar level was seen in both Ringer Lactate and Hydroxy Ethyl Starch group. Hydroxyl ethyl starch produces a rise in blood sugar level to a variable degree according to the concentration, molecular weight and extent of substitution. There is no appreciable effect on serum sodium and chloride level while there is a marked drop in serum calcium and potassium in balanced salt solution Ringer Lactate as well as in all Saline based different generation Hydroxyl ethyl starch groups which was evident even up to 12 hours. 3% pentastarch 200 produces the least disturbances in serum calcium and serum potassium level.

 

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