Vol.5, No.11A, 35-41 (2013) Health
http://dx.doi.org/10.4236/health.2013.511A1005
Renal function after laparoscopic cholecystectomy
and analgesia with tramadol and dipyrone or
ketorolac
Tiago Pechutti Medeiros1, Pedro Thadeu Galvão Vianna2, Leopoldo Muniz da Silva3,
Lídia Raquel de Carvalho4, Gilberto Elias Wady5, Leandro Gobbo Braz2,
Yara Marcondes Machado Castiglia2*
1Graduate Program in Anesthesiology, Botucatu Medical School, UNESP-Universidade Estadual Paulista, Botucatu, Brazil
2Department of Anesthesiology, Botucatu Medical School, UNESP-Universidade Estadual Paulista, Botucatu, Brazil;
*Corresponding Author: yarac@fmb.unesp.br
3São Luiz Hospital, São Paulo, Brazil
4Department of Biostatics, Institute of Biosciences, UNESP-Universidade Estadual Paulista, Botucatu, Brazil
5Mercy Hospital, São Carlos, Brazil
Received 4 September 2013; revised 12 October 2013; accepted 28 October 2013
Copyright © 2013 Tiago Pechutti Medeiros et al. This is an open access article distributed under the Creative Commons Attribu-
tion License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
ABSTRACT
Background: Laparoscopic cholecystectomy (LC)
reduces surgical trauma and hospital stay, but
requires effective and safe postoperative anal-
gesia. This prospective and double-blind study
investigated the effects of analgesia with tra-
madol combined with either dipyrone or keto-
rolac on the postoperative renal function of pa-
tients submitted to LC. Methods: Pre- and post-
operatively (PO), estimated glomerular filtration
rates (GFR), obtained by two formulas depend-
ent on blood Cr and one on blood cystatin C
values, and tubular enzymuria—alkaline phos-
phatase (AP), γ-glutamiltransferase (γ-GT)—
were determined in well hydrated patients who
underwent LC and analgesia with tramadol com-
bined with either dipyrone (Dipyrone, n = 63) or
ketorolac (Ketorolac, n = 63). Upon discharge
from the post-anesthetic care unit (PACU), pain
(through Verbal Numerical Scale—VNS) and
need for rescue analgesia with morphine were
evaluated. Results: There was hemodilution PO,
which made GFR profile analysis more diffi-
cult—those dependent on Cr increased and sta-
tistically correlated, but those dependent on
cystatin C did not change. There was a signifi-
cant PO increase in AP in the Dipyrone and Ke-
torolac groups, and in the product of the both
enzymes in the Ketorolac group. Upon PACU
discharge, the Dipyrone group showed signifi-
cantly higher VNS scores than the Ketorolac
group. All patients received morphine PO, and
the total dose needed for pain control differed
between groups, but without statistical signifi-
cance. Conclusions: The association of trama-
dol with dipyrone or ketorolac in well hydrated
patients submitted to LC had similar analgesic
effectiveness in the PACU. Postoperatively, the
effect on GFR may have been masked by hemo-
dilution, and enzymuria was discreetly enhanced
when ketorolac was used.
Keywords: Kidney Function Tests;
Pneumoperitoneum; Biological Markers; Cystatin C;
Ketorolac; Analgesia
1. INTRODUCTION
Renal venous pressure, hydrostatic pressure and glo-
merular filtration rate (GFR) are adversely affected by
pneumoperitoneum. However, expansion of the extra-
cellular volume can be beneficial to renal function [1-3].
Pain after laparoscopic surgery is multifactorial and may
be quite intense. Current pain management relies on a
number of strategies, including the concomitant use of
opioids and anti-inflammatory drugs [4].
Remifentanil, a synthetic opioid used in anesthesia,
has a predictable duration of action (elimination half-life
of 8 - 20 minutes) because it is metabolized via plasma
esterases [5]. While reducing opioid-induced adverse ef-
Copyright © 2013 SciRes. OPEN ACCESS
T. P. Medeiros et al. / Health 5 (2013) 35-41
36
fects, remifentanil does not provide residual analgesia at
the immediate postoperative period. Tramadol is a cen-
trally acting analgesic that consists of two enantiomers,
both of which contribute to analgesic activity via dif-
ferent mechanisms: (+)-tramadol and the metabolite
(+)-0-desmethyl-tramadol are agonists of μ opioid re-
ceptor. (+)-tramadol inhibits serotonin re-uptake, and
()-tramadol inhibits norepinephrine re-uptake, increas-
ing the inhibitory effects on pain transmission in the
spinal cord [6]. It is excreted via the kidney (over 30%),
and in bolus doses and various injections it does not affect
renal blood flow in normal rats [7]. Tramadol and non-
steroidal anti-inflammatory drugs (NSAID) have often
been combined for the clinical treatment of post-operative
pain. However, the stimulation of opioid receptors may
increase pain sensitivity immediately after opioid admi-
nistration (opioid-induced hyperalgesia). Therefore, in-
vestigating the effects of combining opioids with non-
opioid analgesics, including NSAIDs, would be of espe-
cial interest for anesthesia researchers [8].
NSAIDs block the enzyme cyclooxygenase (COX)
and, in consequence, the synthesis of renal vasodilator
prostaglandins (PG) [9], which help maintain renal blood
flow and GFR, modulating the vasoconstrictor effects of
angiotensine II or norepinephrine [10]. However, in rats
anesthetized with sodium pentobarbital, the NSAID ke-
toprofen, administered early after hypotension due to
hemorrhage, caused fewer changes in renal function and
hystology than the barbituric [11].
Serum cystatin C level, an early marker of mild GFR
deterioration [12], is a useful endogenous alternative to
estimate GFR. However, in a study including 8058
individuals aged 25 - 75 years, besides not being superior
to creatinine in measuring GFR, serum cystation C
seemed to be influenced by factors other than kidney
function alone [13]. To measure the integrity of tubular
cells, assessing urinary concentrations of renal enzymes
is a sensitive non-invasive method. These renal enzymes
are located on specific sites of the kidney: γ-gluta-
myltransferase (γ-GT) is mainly found in the tubules near
the loop of Henle, while alkaline phosphatase (AP) is
found in the epithelial cells of the proximal tubule [14].
As such, once serum creatinine, cystatin C and urinary
enzymes are determined, results that would possibly
quantify perioperative injury to the kidneys may be
obtained.
Thus, the aim of this clinical prospective trial was to
assess the effects of two analgesia regimens on post-
operative renal function in patients submitted to general
anesthesia for laparoscopic cholecystectomy.
2. METHODS
This was a randomized, placebo-controlled, double-
blind trial. After Institutional Review Board approval,
written informed consent was obtained from a total of
126 patients scheduled for general anesthesia for elective
laparoscopic cholecystectomy with CO2 pneumoperito-
neum at 13 mmHg for chronic cholecystitis due to
cholelithiasis. Patients older than 60 years, allergic to
NSAIDs or opioids, with an ASA physical status of more
than III, plasma creatinine higher than 1.5 mg/dl or heart
failure, and users of nephrotoxic drugs were excluded.
Oral 15 mg midazolam was given as pre-medication to
all patients, one hour before anesthesia. Patients were
included in one of two groups: Dipyrone group—re-
ceived placebo (saline) intravenously (iv) at the time of
pre-medication, and 100 mg tramadol with 2 g dipyrone,
iv, approximately 30 min before the end of anesthesia for
analgesia; Ketorolac group—received 30 mg ketorolac,
iv, at the time of pre-medication, and 100 mg tramadol
with 30 mg ketorolac, iv, approximately 30 min before
the end of anesthesia for analgesia. The placebo and
ketorolac solutions were administered by a nurse, who
prepared them in an identical volume (10 ml). The same
nurse prepared the drugs for postoperative analgesia, so
that the double-blind condition of the study was main-
tained.
In the operating theater, all patients were monitored
with electrocardioscopy, pulse oxymeter and non-inva-
sive arterial pressure measurement. All patients were
given 10 ml/kg/h Ringer lactate solution. At this time
point (T1), 20 ml of blood were collected for the labora-
tory assessment of cystatin C, by the immunonephe-
lometric method using Dade Behring® reagents and cali-
brators (N Latex Cystatin C, Dade Behring, Deerfield,
USA), urea and creatinine (dry-chemical method), and
albumin by protein electrophoresis. Additionally, 80 ml
of urine (after bladder catheterization) were collected to
dose AP, γ-GT, and creatinine, by the Vitros 950—
Johnson & Johnson® (USA) automation system. Urinary
creatinine concentrations in mg/dl were multiplied by
0.0884 for conversion to mmol/l, and used to eliminate
the effect of urinary dilution: APcreatinine (U/mmol);
γ-GT/creatinine (U/mmol); AP × γ-GT/creatinine (U/mmol).
Twenty four hours after the end of anesthesia and sur-
gery (time point T2), 20 ml of blood and 80 ml of urine
were once more collected, and the same laboratory as-
says were repeated.
2.1. Anesthesia Procedures
Anesthesia was induced with intravenous 0.5 μg/kg/min
remifentanil, 2 mg/kg propofol, and 0.6 mg/kg rocur-
onium. After tracheal intubation to perform general
anesthesia, intermittent positive pressure ventilation was
continued, and end-tidal carbon dioxide pressure was
monitored to remain around 33 mmHg. Anesthesia was
maintained with 0.25 μg/kg/min remifentanil, sevoflu-
rane adjusted according to hemodynamic parameters, 4
Copyright © 2013 SciRes. OPEN ACCESS
T. P. Medeiros et al. / Health 5 (2013) 35-41 37
liters of fresh gas comprising N2O in 50% of O2, con-
trolled breathing and rebreathing with a semiclosed sys-
tem.
Analgesia in patients from both the Dipyrone and the
Ketorolac groups was assessed by the Verbal Numerical
Scale (VNS) at admission to the post-anesthesia care unit
(PACU), and at every 15 minutes until discharge, at least
two hours after admission to the PACU. According to
instructions received before anesthesia and surgery, pa-
tients rated pain on a zero-ten scale where: zero =
absence of pain, one (1) = minimum existing pain, and
10 = the worst pain imaginable. In the PACU, when
values were above three in the VNS, 1mg morphine
hydrochloride was administered, iv, every 10 minutes until
pain cessation or VNS = 3. Level of sedation (awake and
cooperative, asleep and cooperative after stimulus, asleep
and uncooperative) and quantity of morphine used were
also assessed in the PACU.
GFR was estimated by the following formulas: GFR-
Larsson (ml/min) [15,16] = 77.24 × [cystatin C1.2623
(mg/l)]; GFR-MDRD (“Modification of Diet in Renal
Disease”) (ml/min/1.73m2) [17] = 170 × (creatinine)0.999
× (age)0.176 × [0.762 if female] × [1.18 if black] ×
(urea)0.17 × (albumin)0.318 and GFR-CG (ml/min) [18] =
(140 – age) × weight/serum creatinine x 72 × [0.85 if
female].
2.2. Statistical Analysis
The exact Fisher test was used to study the association
between group and gender. The Student t test was used
for comparisons between groups regarding age, pre- and
postoperative cystatin C level (Δ cystatin C), and the
amount of morphine used in the PACU. Profile analysis
was used to study the effect of group, time and time ×
group interactions. Correlations between variables were
analyzed by Pearson’s correlation coefficient. Statistical
significance was set at p < 0.05.
3. RESULTS
Duration of anesthesia was 70 min ± 10 in the
Dipyrone group, and 68 min ± 13 in the Ketorolac group
(p = 0.42). Age was 40.9 years ± 12.1 in the Dipyrone
group, and 40.2 years ± 11.5 in the Ketorolac group (p =
0.75). In the Dipyrone and Ketorolac groups, females
represented 73% (46) and 82.5% (52) of the patients,
respectively (p = 0.28). Weight was 71.5 kg ± 13.5 in the
Dipyrone group, and 73.6 kg ± 14.9 in the Ketorolac
group (p = 0.31). It can be said that the groups were
homogeneous (Table 1).
Cystatin C values did not differ between groups (p =
0.30), and time points (p = 0.09), and there was no time
points x groups interaction (p = 0.44) (Tab l e 1 ). Serum
creatinine values were not different between groups (p =
0.62), nor was there time points × groups interaction (p =
0.10). However, there was a difference between time
points (p = 0.00001) (Table 1). Plasma albumin pre-
sented the same profile with no difference between
groups (p = 0.42), without time points × groups interac-
tion (p = 0.27), but showing a difference between time
points (p = 0.0005) (Table 1).
The GFR-Larsson was not different between groups (p
= 0.33), and time points (p = 0.07), and there was no
time points × groups interaction (p = 0.66) (Table 2).
GFR-CG was not different between groups (p = 0.79),
and did not exhibit time points × groups interaction (p =
0.55). However, it was different between time points (p =
0.001) (Table 2). GFR-MDRD was not different between
groups (p = 0.72), and did not exhibit time points ×
groups interaction (p = 0.58), but it differed between
time points (p = 0.003) (Table 2). A significant cor-
relation was observed only between GFR-MDRD and
GFR-CG values at T1 (r = 0.48 and p = 0.000) and T2 (r
= 0.36 and p = 0.000).
AP results significantly differed between groups (p =
0.02) and time points (p = 0.03), and showed time points
× groups interaction (p = 0.001). Thus, Dipyrone group >
Ketorolac group and T1 < T2 (Tab le 2 ). γ-GT presented
a statistically significant difference between groups (p =
0.001), and time points × groups interaction (p =
0.00002), with no difference between time points (p =
0.07). The product of the two enzymes significantly
differed between groups (p = 0.005) and time points (p =
0.008), and showed time points × groups interaction (p =
0.0002) (Table 2).
Table 1. Clinical data of study group patients (Means ± SD).
Parameter
Dipyrone gr oup
(n = 63) Ketorolac group
(n = 63) p
Age (years) 40.9 ± 12.1 40.2 ± 11.5 0.75
Weight (kg) 71.5 ±13.5 73.6 ± 14.9 0.31
Gender F:M 46:17 52:11 0.28
Duration of
anesthesia (min) 70 ± 10 68 ± 13 0.42
T10.83 ± 0.19 0.78 ± 0.18 *0.31
Plasma cystatin
C (mg/l) T20.84 ± 0.18 0.81 ± 0.17 #0.24
T10.78 ± 0.14 0.77 ± 0.16 *0.62
Blood creatinine
(mg/dl) T20.70 ± 0.16 0.73 ± 0.19 #0.00001
T14.1 ± 0.7 4.1 ± 0.5 *0.42
Plasma
albumin (g/dl)T23.3 ± 0.7 3.7 ± 2.5 #0.0005
Δ cystatin
C (mg/ml) 0.0017 ± 0.14 0.0030 ± 0.15 *0.23
* = p between Dipyrone and Ketorolac groups; # = p between time point 1
(T1—at the arriving in operating theater) and time point 2 (T2—24 h after
the end of anesthesia and surgery).
Copyright © 2013 SciRes. OPEN ACCESS
T. P. Medeiros et al. / Health 5 (2013) 35-41
38
Table 2. Markers of renal function for the two groups on ad-
mission in the surgery theater (T1) and after 24 hours of anes-
thesia and surgery (T2) (Means ± SD).
Parameter Dipyrone
group
(n = 63)
Ketorolac
group
(n = 63) p
T1 61.5 ± 19.4 66.7 ± 21.8*0.33
GFR-Larsson (ml/min)
T2 60.2 ± 17.4 61.6 ± 17.0#0.07
T1 114.6 ± 29.5 119.1 ± 29.8*0.79
GFR-CG (ml/min)
T2 127.7 ± 38.2 126.1 ± 32.7#0.001
T1 94.2 ± 32.6 93.7 ± 26.5*0.72
GFR-MDRD
(ml/min/1.73 m2) T2 105.5 ± 42.8 101.6 ± 44.8#0.003
T1 2.7 ± 1.1 2.0 ± 0.3 *0.02
AP/UCr (U/mmol)
T2 3.5 ± 1.6 3.5 ± 0.8 #0.03
T1 4.1 ± 2.0 5.0 ± 1.2 *0.001
γ-GT/UCr (U/mmol)
T2 3.3 ± 1.8 5.5 ± 2.5 #0.07
T1 134.2 ± 68.4 86.3 ± 22.0*0.005
AP × γ-GT/UCr
(U/mmol) T2 85.1 ± 45.8 167.0 ± 83.8#0.008
GFR = glomerular filtration rate; AP = alkaline phosphatase; γ-GT =
γ-glutamiltransferase; UCr=urinary creatinine; * = p between Dipyrone and
Ketorolac groups; # = p between time points T1 and T2.
All patients were awake at PACU admission. VNS
scores gradually decreased with time for all patients, but
groups differed at PACU discharge, when the Dipyrone
group mean score (2.0 ± 1.7) was higher than that of the
Ketorolac group (1.6 ± 1.6) (p = 0.04). All patients re-
ceived morphine in the postoperative period and the total
dose needed for pain control differed between groups
(0.95 mg ± 1.55 and 0.71 mg ± 1.21 for the Dipyrone and
the Ketorolac groups, respectively). Such difference,
however, did not reach statistical significance (p = 0.34).
4. DISCUSSION
Hypovolemia in combination with high intraab-
dominal pressure may lead to restrictive flow to vital
organs such as the kidney. During pneumoperitoneum at
12 mmHg, compressive effects on the renal parenchyma,
renal vessels and inferior vena cava reduce effective
renal plasma flow, GFR, sodium excretion and urine
output [19,20]. In a porcine model, volume expansion
with 15 ml/kg/h isotonic solution could reverse the
adverse effects of prolonged (4 hours) CO2 pneumo-
peritoneum (15 mmHg) on renal blood flow and urine
output [1]. When pneumoperitoneum is associated with
NSAID administration and pre-existent kidney disease,
acute renal failure may occur. Nevertheless, the use of
NSAID can be safe in well hydrated patients without
previous renal dysfunction [21], while in patients with
normal preoperative renal function it may cause a
transitory decrease of 16 ml/min in GFR in the early
postoperative period [22]. The patients included in this
study presented normal plasma creatinine and were sub-
mitted to 13 mmHg pneumoperitoneum, but they were
well hydrated during anesthesia.
GFR needs to be reduced 75% before serum creatinine
reaches abnormal levels [23] and blood creatinine con-
centration is affected by other factors that do not depend
upon renal function or injuries [24]. In this study, serum
creatinine decreased in both groups in the postoperative
period, probably due to hemodilution caused by intra-
operative fluid loading and release of antidiuretic hor-
mone, considered as a stress hormone that acts to main-
tain homeostasis [25-27]. According to the Cockcroft &
Gault formula [18], that estimates creatinine clearance, a
postoperative GFR increase might have occurred in both
groups as creatinine concentrations decreased. Did kid-
ney function improve postoperatively in these patients?
Albumin concentrations also decreased in both groups
over the same period, and this speaks in favor of hemo-
dilution in the postoperative period [28], holding it res-
ponsible for the decrease in creatinine and increase in its
clearance. Since there was a positive correlation between
the Cockcroft & Gault method and the MDRD method,
that also uses serum creatinine—and albumin—results,
the GFR values obtained by both methods may be
overestimated. Thus, no change in the concentration of
the endogenous marker could be observed unless an
important renal injury exceeding the dilution factor had
occurred.
No significant difference was found between pre-
operative and postoperative cystatin C in both groups. If
there had been hemodilution and no decrease in cystatin
C values, can one infer that these values would have
indeed increased? Because cystatin C changes in these
patients before creatinine over the postoperative period,
would then a decrease in GFR have occurred? After
filtration by the glomerulus, cystatin C is reabsorbed and
catabolized (without secretion) by tubular epithelial cells,
and only insignificant amounts are excreted in the urine
[29]. As a consequence, although cystatin C is cleared by
the kidneys, its urinary clearance is not routinely
measured. Cystatin C would be a better marker of renal
function than plasma creatinine [30,31]—its production
seems to be less variable between patients than that of
creatinine. However, there is evidence that serum cys-
tatin C levels are influenced by corticoid use, and by
thyroid function. Cystatin C levels appear to be related to
age, gender, weight, height, tobacco smoking status, and
C reactive protein concentration [32,33]. Δ cystatin C
(between pre and postoperative values of each group)
showed no significant difference. However, it was greater
in the group that received ketorolac. Further research is
Copyright © 2013 SciRes. OPEN ACCESS
T. P. Medeiros et al. / Health 5 (2013) 35-41 39
needed to find out whether this is clinically relevant.
In this study, the endogenous biomarkers of renal
injury AP and γ-GT were dosed in urine. The increased
secretion of both markers, that takes place before serum
creatinine increases, indicates injury in the brush border
membrane and loss of the microvilli structure. In rats
submitted to an excessive dose of paracetamol (leading
to acute proximal tubular injury), the urinary levels of
these enzymes significantly increased in the first 24
hours, and returned to nearly baseline values after 48 - 72
hours, while GFR drastically decreased [34].
Our results show that urinary AP increased 24 h after
surgery in both groups, indicating alteration in the tu-
bular cells after surgery, apparently not related to ke-
torolac use. In the group that did not receive NSAID, AP
values were higher at both time points studied. The
concentration of γ-GT did not significantly change in the
postoperative period in both groups, and in contrast with
AP, it remained higher in the Ketorolac group. The product
of both urinary enzymes showed a different profile in
both groups and time points. In the Dipyrone group, the
product was significantly higher preoperatively, but it de-
creased in the postoperative period. In patients receiving
ketorolac, urinary enzyme product was significantly in-
creased postoperatively. Whether such increase indicates
some degree of injury at the brush border membrane of
the tubular cell is not clear. Further studies are necessary
to substantiate and better explain these results.
The difference in preoperative enzyme results observed
between groups may be due to individual differences in
creatinine excretion (the common denominator). This
may be affected by various factors such as age, gender,
race, body habits, obesity, chronic disease (poor nutrition,
inflammation, lack of conditioning when bedridden, neu-
romuscular disease) and diet [35]. On the other hand, it is
noteworthy that patients in the Ketorolac group at T1 had
already received ketorolac at least 60 minutes earlier.
The consequences of preoperative stress in this group
would then be milder, hence less urinary enzyme released.
The cross-talk mechanism involving the afferent and
efferent arterioles and the renal tubules has been de-
monstrated. Such relation would be more intense than
expressed by the anatomical contact between these struc-
tures, and has been known for a long time as the jux-
taglomerular apparatus. Thus, decreased stress and stress
hormones may indirectly influence the tubules by acting
on these renal capillaries [36].
Ketorolac given as a pre-medication drug (0.5 mg/kg)
in gynecological laparoscopy has been reported to
influence the response of white blood cells, which is
usually affected by surgical stress [37]. Administered
intravenously, 15 mg ketorolac followed by 7.5 mg/h, in
elective cesarean section, eased hemodynamic response
to stress of tracheal intubation, improving the quality of
analgesia and determining lower concentrations of plas-
ma cortisol [38]. Ketorolac reaches maximum plasma
concentration in 45 minutes and analgesic peak in one or
two hours with an increased peak in aged patients with
impaired renal function. In a study of 40 dogs submitted
to hysterectomy and oophorectomy under general anes-
thesia, ketorolac was administered as one of the anal-
gesics for treatment of postoperative pain (0.5 mg/kg).
The analysis of serum creatinine and urea and renal
function biomarkers such as γ-GT and AP showed that
ketorolac is safe for this purpose [39].
In this study, good results were achieved using ana-
lgesia for pain control in both groups. According to VNS,
only a small amount of rescue analgesia (morphine) was
needed. Treatment with ketorolac as a premedication
may ease renal response to preoperative stress. Addi-
tionally, low-dose ketorolac instillation into wounds has
been demonstrated to modulate local inflammatory events,
decrease postoperative pain, and reduce opioid con-
sumption, suggesting that the administration of NSAIDs
into surgical wounds may be an analgesic alternative to
higher systemic dosing of NSAIDs [40].
In conclusion, both analgesia regimens used in this
study that combined tramadol with either dipyrone or
ketorolac, in well hydrated patients submitted to laparo-
scopic cholecystectomy, showed similar results in the
PACU. Postoperatively, the effect on GFR might have
been masked by hemodilution, but there was a discreet
increase in the release of renal tubular enzymes when
ketorolac was used, a response that requires further clari-
fication.
5. ACKNOWLEDGEMENTS
Grant 07/51101-0—São Paulo Research Foundation (FAPESP); TP
Medeiros was granted a scholarship from CAPES.
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