Insulin and sepsis.
Post-operative infection is a significant cause of morbidity and mortality. Despite vigorous attempts to control the bacterial "seed" of infection by asepsis and antibiotics, infection is still the greatest enemy of surgeons. Hence, more attention is now being focussed on the "soil" or host factors and their contribution to postoperative infection. Numerous workers have confirmed hyperglycemia as a metabolic response to operative stress,,,, which was first demonstrated in dogs in 1877 by Claude Bernard. According to Wright, the effects of injury are associated with a rise in growth hormone, cortisol, catecholamines and glucagon and their effects on intermediate glucose metabolism within the cell, reducing glucose uptake. Insulin appears to have diminished responsiveness and it may well be that the liver may be set at a higher level in its function as a regulator of blood glucose. The per- and post-operative inhibition of insulin secretion has also been demonstrated by Aarimaa et al.
In view of all the above, the present study was undertaken to determine whether per- and post-operative insulin administration had any effect on postoperative infection and infection-related mortality.
Ninety-three consecutive patients operated upon in a surgical unit of K.E.M. hospital, Bombay, India, over a 6 month period were selected for this study.
The youngest patient was 13 years old and the oldest was 74 years with the mean age of 30 years. Seventy per cent of the patients were males. The weights of all the patients ranged from 25 kg to 70 kg with an average weight of 45 ± 5 kg.
These patients were allocated to one of the two groups (1) controls (2) insulin treated group. Each group was further divided into routine major (RM) and emergency (E) cases. The control group of 47 cases consisted of 11 RM and 36 E cases, while the insulin treated group of 46 cases was made up of 23 RM and 23 E cases.
The RM cases in both groups included. highly selective vagotomies, gastrojejunostomies, gastrectomies, cholecystectomies, Freyer's prostatectomies, thyroidectomies, and radical mastectomies. The E cases included acute abdomens with or without peritonitis and also traumatic cases involving exploratory laparotomy.
A pre-operative reading for blood sugar and urine sugar was obtained in all the cases. In order to avoid possible hyperglycemia, pre-operative administration of glucose containing fluids was avoided in the cases receiving insulin. Glucose containing fluids were administered as required pre-operatively to the E control group of patients. This was done because our initial hypothesis was that it was the per-operative and post-operative hyperglycemia that might make the difference between these two groups of patients. In the RM cases, pre-operative fluid administration was not required.
Intra-operatively, the control group received standard IV fluids (5% glucose, glucose-saline, blood, plasma expanders). For the insulin group, during surgery, two infusions were maintained either separately or through a three-way connection. One comprised glucose (10% in water), insulin (24 units plain) and potassium (20 mEq of KCI) drip at a constant rate adjusted to provide around 250, mg/kg/hour of glucose and 0.12 units insulin/kg/hour. The other drip was used to infuse glucose free solutions to combat operative fluid losses and shock.
In both the groups, immediately at the end of surgery, readings of blood and urine sugar were once again obtained.
In the post-operative period, the control group again received standard IN. fluids (as above), and on withdrawal of I.V. fluids they were kept on a normal hospital diet but insulin was not administered. Post-operatively, the insulin group patients were given around 7-10 gm of glucose/kg/24 hours and the insulin dosage (approximately 12-16 units plain by I.V. drip) was adjusted to keep urine sugar at nil and blood sugar between 100-150 mg%. Blood sugar levels were obtained twice daily and urine sugar was monitored 4-6 hourly to avoid hypohyper-glycemic episodes. On withdrawal of I.V. fluids, all the insulin group cases were given ? to ½ unit lente insulin/kg subcutaneously as a single daily early morning injection till the removal of all sutures (7-10 days).
All 93 cases were weighed daily till the day of discharge.
All the R.M. cases received only 2 doses of I.V. 1 gm chloramphenicol, first dose at the time of commencement of surgery and the second, 6 hours after the first one. Further, antibiotics were given if and when there was clinical evidence of sepsis or when the CVP line or Foley's catheter tip grew organisms in a patient who had not settled clinically. All the E cases received initially I.V. chloramphenicol 500 mg 6 hourly and continuation of chloramphenicol or change to other antibiotics was determined either by the clinical course of the patient or by the sensitivity pattern of the isolated organisms from the CVP line or Foley's catheter tip, peritoneal fluid and wound swabs.
All the 93 cases were analysed from the following points of view post-operatively.
1. Immediate post-operative blood and urine sugar readings.
2. Infection in the form of wound infection and dehiscence, burst abdomen, peritonitis, residual abscesses, and septicaemia.
3. Post-mortem examination was performed in all patients who died in order to determine the infection related mortality.
None of our 93 cases studied had preoperative blood sugar levels above 150 mg%.
[Table - 1] analyses our results. The infection rate was significantly lower in patients receiving insulin. The infection-related mortality was lower in patients receiving insulin, in the total number of cases and in the RM cases. The difference in the infection-related mortality rates between insulin and the control group was not significant in the emergency cases.
The infection rate and infection-related mortality rate did not correlate with the blood sugar level postoperatively in both the control and insulin groups.
Despite the availability of newer antibiotics and the introduction of more stringent aseptic measures, our infection and infection-related mortality rates over the past 5 years stubbornly remained very high (our unpulished data). These figures along with the realization that more and more endogenous organisms were cultured, made it painfully obvious that no amount of exogenous measures could replace a normal host environment.
One of the most commonly encountered conditions with a very high predilection for infection is diabetes mellitus. With this in mind and considering the diabetes like state of glucose metabolism in the pre and post-operative periods.,,,, probably because of elevated anti-insulin hormones and the per-operative and post-operative suppression of insulin secretion, it was logical, to study if preoperative and post-operative insulin administration had any bearing on postoperative infection and infection-related mortality. As regards the protective role of insulin in infection and wound healing, though clinical studies are lacking, numerous animal experiments have been reported to highlight the importance of insulin in cellular growth and wound healing.
The glucose insulin potassium solution was prepared on the following basis: (1) 10% glucose was selected since at that time, it was the only guaranteed, pyrogen free, I.V. fluid available in our hospital; (2) the insulin dose (0.12 units plain insulin/kg/hour) was adjusted according to the usual formula of 1 unit plain insulin per 2 gm of glucose; (3) potassium chloride (20 mEq per 500 ml of fluid) was administered to counteract the glucose insulin-induced hypokalemia.
Numerous studies,, have shown that the maximal speed of glucose administration without exceeding metabolic capabilities and producing glucosuria and hyperglycemia, ranges from 200 to 500 mg/kg/hour, and even this varies in an individual patient under different conditions. 250 mg/kg/hr. glucose administration was selected for pre-operative infusion since during sleep, the basal metabolic rate is one calorie/kg/hour. There are no reported values for minimum glucose administration during anaesthesia. Postoperatively, our patients were again maintained on approximately 7-10 gm of glucose/kg/day to ensure adequate calories and insulin was given to minimize the nitrogen breakdown.
This study suggests that post-operative infection was lowered in insulin-treated cases. Infection related mortality was lowered in routine major cases but the same could not be said of the emergency cases. Whether this was related to the control of blood sugar levels is not clear, because no correlation between blood sugar levels and infection or infection related mortality could be demonstrated. Obviously, further studies are needed to exactly delineate the role and the optimal dose of insulin in post-operative infection.
We would like to thank the Dean, K.E.M. Hospital, Bombay, India for allowing us to use and publish the hospital data.