Vol. 42 (1): 69-77, January - February, 2016
ORIGINAL ARTICLE
doi: 10.1590/S1677-5538.IBJU.2014.0677
Ischemia modified albumin: does it change during
pneumoperitoneum in robotic prostatectomies?
_______________________________________________
Serpil Ustalar Ozgen 1, Bora Ozveren 2, Meltem Kilercik 3, Ugur Aksu 4, Binnaz Ay 5, Ilter Tufek 2, Ali Riza
Kural 6, Levent N.Turkeri 7, Fevzi Toraman 1
1
Department of Anesthesiology and Reanimation, Acibadem University, Istanbul, Turkey; 2 Department
of Urology, Acibadem University, Istanbul, Turkey; 3 Acibadem Labmed, Istanbul, Turkey; 4 Department
of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey; 5 Department of Anesthesiology,
Acibadem Maslak Hospital, Istanbul, Turkey; 6 Clinics of Urology, Acibadem Maslak Hospital, Istanbul,
Turkey; 7 Clinics of Urology Acibadem Kadikoy Hospital, Istanbul, Turkey
ABSTRACT
ARTICLE INFO
______________________________________________________________
______________________
Background: The unique positioning of the patient at steep Trendelenburg with prolonged and increased intra-abdominal pressure (IAP) during robotic radical prostatectomy
may increase the risk of splanchnic ischemia. We aimed to investigate the acute effects
of IAP and steep Trendelenburg position on the level of ischemia modified albumin
(IMA) and to test if serum IMA levels might be used as a surrogate marker for possible
covert ischemia during robotic radical prostatectomies.
Patients and Methods: Fifty ASA I-II patients scheduled for elective robotic radical
prostatectomy were included in this investigation.
Exclusion criteria: The patients were excluded from the study when an arterial cannulation could not be accomplished, if the case had to be converted to open surgery or if
the calculated intraoperative bleeding exceeded 300ml.
All the patients were placed in steep (45 degrees) Trendelenburg position following
trocar placement. Throughout the operation the IAP was maintained between 1114mmHg. Mean arterial blood pressure (MAP), cardiac output (CO) were continuously
monitored before the induction and throughout the surgery. Blood gases, electrolytes,
urea, creatinine, alanine transferase (ALT), aspartate transferase (AST) were recorded.
Additionally, IMA levels were measured before, during and after surgery.
Results: (1) MAP, CO, lactate and hemoglobin (Hb) did not significantly change in any
period of surgery (p>0.05); (2) sodium (p<0.01), potassium (p<0.05) and urea (p<0.05)
levels decreased at postoperative period, and no significant changes at creatinine, AST,
ALT levels were observed in these patients; (3) At the end of surgery (180 min) pCO2,
pO2, HCO3 and BE did not change compared to after induction values (p>0.05) but mild
acidosis was present in these patients (p<0.01 vs. after induction); (4) IMA levels were
found to be comparable before induction (0.34±0.04), after induction (0.31±0.06) and
at the end of surgery (0.29±0.05) as well.
Conclusion: We did not demonstrate any significant mesenteric-splanchnic ischemia
which could be detected by serum IMA levels during robotic radical prostatectomies
performed under steep Trendelenburg position and when IAP is maintained in between
11-14 mmHg
Key words:
Ischemia; Albumins; Head-Down
Tilt; Robotics; Prostatectomy
69
Int Braz J Urol. 2016; 42: 69-77
_____________________
Submitted for publication:
December 30, 2014
_____________________
Accepted after revision:
August 12, 2015
IBJU | ISCHEMIA MODIFIED ALBUMIN, ROBOTIC PROSTATECTOMY
duction. Endothelial or extracellular hypoxia, acidosis, and free oxygen radicals have been shown
to cause IMA increase (20, 21), thus IMA can be
detected early on the beginning of ischemia. Moreover IMA was found to increase in patients with
mesenteric ischemia (22). It has been identified as
a helpful marker for determining the alterations in
the splanchnic and the visceral blood flow during
laparoscopic cholecystectomies (23).
After myocardial ischemia, the serum levels of IMA rise within minutes and continue to
increase for 6-12 hours, after which they return
to normal (24-28). Increase in IMA concentrations
has also been shown to indicate tissue ischemia in
other conditions such as peripheral vascular disease, exercise-induced skeletal muscle ischemia,
end-stage renal disease patients on haemodialysis,
acute stroke, calf-muscle ischemia (29-33).
In the present study, we aimed to investigate the acute effects of IAP and steep Trendelenburg position on the level of ischemia modified albumin (IMA) and to test if serum IMA levels might
be used as a surrogate marker for possible covert
ischemia during robotic radical prostatectomies.
INTRODUCTION
Robot assistance in laparoscopic surgery
has undoubtedly contributed to the advancement
of minimally invasive oncologic surgery. Robotic
surgery provides a number of potential benefits
such as improvement in surgical precision, diminished blood loss, reduced postoperative pain,
improved cosmetic outcome, shorter convalescence and hence improved patient satisfaction (1, 2).
Robot assisted laparoscopic radical prostatectomy
(RARP) is the most frequently performed robotic
procedure in urology. Despite the established advantages, there are several important issues related to the intra-operative management specific to
this procedure. The positioning of patients during
RARP impacts the risks related to hemodynamic
changes such as increased systemic vascular resistance (SVR), mean arterial pressure (MAP), filling
pressures and reduction in cardiac index (CI) (3, 4).
High intra-abdominal pressure (IAP), especially if
over 15mmHg, increases cerebral blood flow and
intracranial pressure, while decreasing portal, hepatic vein flow and the total hepatic microcirculation (5-8). Increased IAP furthermore decreases
mesenteric blood flow and impedes gastrointestinal microcirculation (8, 9). The pneumoperitoneum (PP) similarly leads to decreased arterial and
venous flow in renal medulla and cortex (10-12).
The fixed positioning of the patients followed by the docking of the robot in steep Trendelenburg position and the relatively long duration
of this procedure can thus cause excessive mechanical pressure over the gastrointestinal, respiratory and the cardiovascular systems, increase
the risk of hypothermia, intensify the hemodynamic and respiratory adverse effects of the PP and
may as well give rise to mesenteric-splanchnic
hypoxic ischemia (4).
Serum ischemia modified albumin (IMA) is
a new, FDA approved biomarker of ischemia, and
increases in patients with acute coronary syndrome (13-16). IMA is produced during an ischemic
attack and is present in blood in easily detectable concentrations (13, 17-19). Hypoxia, acidosis
and free radical production reduce the ability of
human serum albumin to bind metals like cobalt
to its N-terminus, which in turn causes IMA pro-
MATERIALS AND METHODS
Local ethics committee approval for
this study (ATADEK No: 2013-456/B.30.2.A
CU.0.00.00.050-06) was provided by ATADEK,
Acibadem University, Ethics Committee, Istanbul,
Turkey on 01 February 2013.
Fifty male patients, aged 55-75 years, ASA
I-II, scheduled for RARP were included in the study and informed consents were taken.
Exclusion Criteria: The patients were excluded from the study when an arterial cannulation could not be accomplished, if the case had to
be converted to open surgery or if the calculated
intraoperative bleeding exceeded 300ml.
General Procedure
All patients were pre-medicated with midazolam 0.05mg/kg intravenously (i.v.) and standard monitorization, including, electrocardiography (ECG), invasive blood pressure (IBP), pulse
oximetry (SpO2), regional cerebral oxygenation
(rSO2), cardiac output (CO), and end tidal carbon
70
IBJU | ISCHEMIA MODIFIED ALBUMIN, ROBOTIC PROSTATECTOMY
dioxide (ETCO2), was applied. Anaesthesia induction was performed by propofol 2.5-3.5mg/kg, remifentanil 1mic/kg i.v. and muscle relaxation was
performed by rocuronium bromide 0.6mg/kg i.v.
bolus and infusion 4-15mcg/kg/min. Anaesthesia
was maintained by remifentanil 0.025-0.05mic/
kg/min i.v.infusion and by sevoflurane 0.8-1% in
O2:N2O/40:60 in all patients. PEEP was adjusted
between 4.6-4.8mmHg. The patients were placed in steep Trendelenburg position (45 degrees
head-down angulation) after trocar placement
and until the robot was un-docked. The IAP was
maintained between 11-14mmHg throughout the
laparoscopic stage of the operation.
MAP and CO were measured constantly as
systemic hemodynamic parameters and recorded
at particular instants: (1) before induction (BI);
(2) after induction (AI); (3) 5thmin; (4) 60thmin; (5)
90thmin; (6) 120thmin; (7) 150thmin; (8) 180thmin
of PP. Arterial blood levels of lactate, hemoglobin,
pH, pCO2, pO2, HCO3- and base access were monitored at same intervals. Additionally, serum sodium,
potassium, blood urea nitrogen (BUN), creatinine,
alanine transferase (ALT) and aspartate transferase
(AST) were assessed preoperatively and postoperatively. Blood was sampled for interim measurements of serum ischemia modified albumin levels before induction (BI), after induction (AI) and
the end of surgery (ES). The serum samples were
stored at -20 degrees until they were sent to laboratory for IMA quantification. All of the serum
samples for IMA measurements remained intact.
ter gentle shaking, 10 minutes were waited to allow
cobalt binding to albumin. Then 50uL dithiothreitol
(DTT) (Sigma) was added as a colouring agent. As
control, 50uL of distilled water was used instead of
DTT. After 2 minutes, 1mL of 0.9% NaCl was added
to stop the reaction, and the absorbance at 470nm
was determined using a spectrophotometer (24). The
difference of absorbance units between control and
DTT samples were recorded. The results were quantified as absorbance unit (ABSU) and values greater
than 0.400 ABSU were accepted as showing lower
binding capacity for cobalt, therefore indicative of
ischemia, whereas values lower than 0.400 ABSU
were interpreted as lack of ischemia (24, 25).
Statistical analysis
Outcomes were reported as the mean±SEM.
Statistical analysis was performed using GraphPad
Prism version 5.0 for Windows (GraphPad Software, La Jolla, Calif). Results were compared using
repeated measures ANOVA-tukey post hoc test
used and a p-value of <0.05 was considered statistically significant.
RESULTS
The descriptive characteristics of patients
and duration of surgery is summarized in Table-1.
Systemic hemodynamics results
The systemic hemodynamic values are
presented in Figure-1. Induction of anaesthesia
did not cause a statistically significant effect
on MAP (p>0.05). Likewise, CO values were not
affected by anaesthesia. At any time of surgery,
both MAP and CO values were found to be similar compared to their respective levels after
anaesthesia induction (p>0.05).
Determination of Ischemia modified Albumin
(IMA)
IMA levels were determined according to the
method defined by Bar-Or et al. (24). Briefly, 200uL
serum was added to 50uL 0. 1% (w/v) cobalt chloride (Sigma Aldrich, St. Louis, MO; CoCl2.6H2O). Af-
Table 1 - Characteristics of the patients and duration of pneumoperitoneum(PP).
Age
59.7±1.3
Height (cm)
Weight (kg)
BSA
PP. duration (min.)
171.2±3.0
81.9±1.7
1.95±0.04
186.5±6.54
(Acibadem Kadikoy /Maslak Hospital, 2013)
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IBJU | ISCHEMIA MODIFIED ALBUMIN, ROBOTIC PROSTATECTOMY
Blood gases analysis results
Blood gasses and related parameters are
presented in Figure-2 and Table-2. The arterial pH
was more acidotic at the 150th and 180thmin of
PP when compared to 5thmin of PP. pCO2 values
were also found higher concurrently. pO2 values
were higher preoperatively than the pre-induction
values during PP. While HCO3- level was not statistically different, base excess (BE) levels were higher at 60th, 120th and 180thmin. Hemoglobin and
lactate values were not statistically altered during
the operation.
vels of sodium, potassium and urea were lower
(p<0.01, p<0.05, p<0.05; respectively), whereas,
postoperative levels of creatinine, ALT and AST
were not different from the preoperative values
(p>0.05).
Routine biochemistry and plasma electrolyte results
Plasma ions, urea, creatinine, ALT, AST
levels are presented in Table-3. Postoperative le-
DISCUSSION
IMA levels results
IMA assessments at three time intervals
are presented in Figure-3. Mean IMA (ABS unit)
values were 0.34±0.04, 0.31±0.06 and 0.29±0.05.
The variances between intervals were not found to
be statistically significant (p>0.05) (Figure-3).
RARP is performed while the patient is
uniquely placed in a 45 degrees head-down (Tren-
Figure 1 - Systemic hemodynamic parameters.
Figure 2 - Lactate and hemoglobin values at all-time points.
72
IBJU | ISCHEMIA MODIFIED ALBUMIN, ROBOTIC PROSTATECTOMY
Table 2 - Blood Gases parameters.
BI
5 th min
AI
60 th min
90 thmin
120 thmin
150 th min
180 thmin
pH
7.41
±
0.02
7.41 ± 0.01 7.42 ±
0.01
7.42 ± 0.01 7.37
± 0.01 7.4
±
0.01 7.33c ±
0.03
7.36
±
0.01aabbbcccdd
pCO2
37.8
±
2.8
35.6 ±
0.7
33
±
0.5
32.5b ±
±
±
0.6
43.3
±
2.3bcc
38.5
±
1.4bbbcccd
pO2
140.2 ±
37.3 211.6 ±
14
157
± 8.1aaa
± 16.2 160.8 ±
5.6aa
128
±
8.4
154.7b
±
7.4
153
0.6
39.2
± 5.9aaa 145
2.3 34.3
HCO3- 25.2
±
0.7
22.6 ±
0.3
21.6 ±
0.3
24.6 ±
3.8
22.8
±
0.7 21.2
±
0.3
22.3
±
0.9
21.5
±
0.4
BE (-)
±
1.0
1.3
0.3
1.6
0.3
2.4a ±
0.3
1.4
±
0.7 2.3a
±
0.3
2.3
±
1.2
2.4a
±
0.4
0.8
±
±
(BI = Before induction, AI = After induction, 5th min: 5th min of PP) (aap<0.01, aaap<0.001 vs AI; bp<0.05,bbbp<0.001 vs PP 5th min;ccp<0.01, cccp<0.001 vs PP 60th min;dp<0.05 vs
PP 120th min) (Acibadem Kadikoy /Maslak Hospital, 2013)
Table 3 - Routine blood chemistry parameters .
Pre-op
Na+ (mmol/L)
4.5
±
±
31.7
±
0.9
±
AST (U/L)
22.9
±
1.1
19
±
ALT (U/L)
24.7
±
1.9
21.7
±
K+ (mmol/L)
Urea (mg/dL)
Creatinine (mg/dL)
140
0
0.1
1.3
0
138.2
Post-op
±
0.4**
4.1
±
0.1*
24.2
±
3.7*
0.8
±
0.1
1.9
4.1
(*p<0.05,**p<0.01vs Pre-op)
(Acibadem Kadikoy /Maslak Hospital, 2013)
caused by the exclusive fixed patient-positioning
in addition to the duration of robot-assisted laparoscopic radical prostatectomy. We have come up
with a hypothesis of a possible mesenteric-splanchnic injury during RARP subsequent to a simple
observation of frequent and prolonged post-operative ileus in patients undergoing this operation.
Our purpose was to assess the acute effects of IAP
at steep Trendelenburg position during this operation by hemodynamic monitorization, blood
gas and electrolyte analyses and utilizing serum
IMA as a biomarker for a supposedly overlooked
mesenteric-splanchnic ischemia during robotic
prostatectomies. However, our research failed to
suggest any significant association of this exclusive patient positioning or variances of IAP levels
with mesenteric-splanchnic ischemia as assessed
by means of serum IMA during robotic radical
prostatectomy.
Previous studies evaluating the course of
cardiovascular changes during PP pointed out that
Figure 3 - Serum IMA levels at three time points (BI: Before
induction, AI: After induction, ES: End of surgery).
delenburg) position and requires CO2 insufflation
to maintain an IAP of 12-15mmHg. We designed
this study to investigate a hypothesis that even
with a standard IAP, some form of mesenteric-splanchnic injury might be induced due to an
extra gravitational pressure or a traction force
73
IBJU | ISCHEMIA MODIFIED ALBUMIN, ROBOTIC PROSTATECTOMY
the CI gradually increased and systemic vascular
resistance decreased 10 minutes after CO2 insufflation (35-37). Additionally other studies suggested
that CO rate decreased by 10-30% in Trendelenburg position (37-39). On the other hand, the mean
CO level stayed stable (between 2.4-3.8L/min) in
our study. It decreased to 2.4L/min at 5 minutes of
PP but this change was statistically insignificant.
Lestar et al. examined the circulatory
effects of an extreme Trendelenburg position (45º)
on patients during robot-assisted laparoscopic radical prostatectomy and reported an almost 3-fold
increase in central venous pressure compared with
the initial value. MAP was increased by 35% in
this study whereas heart rate (HR), stroke volume (SV), CO, and mixed venous oxygen saturation
were unaffected during surgery, as were echocardiographic heart dimensions. In the horizontal position after PP exsufflation, filling pressures and
MAP returned to baseline levels (38).
In another study designed to evaluate hemodynamic changes associated with head-down
positioning and prolonged PP during RARP, invasive hemodynamic parameters were measured
by transpulmonary arterial thermodilution using
the PiCCO system with a femoral artery catheter,
CI, HR, MAP, systemic vascular resistance index,
intrathoracic blood volume, and central venous
pressure were recorded with the patient in the supine position, after head-down tilt, intraoperatively after 30 min, 1h, 2hs, 3hs, and 4hs of PP
at an insufflation pressure of 12mmHg. Placing
the patient in the Trendelenburg position caused
a significant increase in CVP, whereas all other
hemodynamic parameters remained nearly unaffected. The induction of PP resulted in a significant increase in MAP whereas no other parameter
was affected. Even at 4 hours of PP, only mild
hemodynamic changes were observed (38). In our
study, MAP was lower compared to pre-induction
values throughout the operation, except a slight
but statistically insignificant increase after PP. In
our study, we did not prefer the use of invasive
cardiac control.
In the present study, the IAP was 14mmHg
at the start of PP and then maintained around
11mmHg for a mean duration of 3 hours. Post-operative levels of AST, ALT were not statistically
different compared to the preoperative values. In
an animal study assessing the effect of prolonged
PP on liver function and perfusion, it was found
that the liver sustained no damage due to prolonged PP during laparoscopic surgery. In that study,
the IAP was maintained at 14mmHg and the mean
operation time was 6 hours (34).
In our study Group, the blood pH values
were significantly lower at 150thmin and 180th min
of PP than other intervals. At the same periods,
pCO2 was also significantly higher compared to
those measurements at other times. This can be
explained by increased CO2 absorption during that
time intervals of PP. In a study assessing the acid-base status and hemodynamic changes during
PP, it was reported that there was a significant
absorption of CO2 gas across the peritoneum which caused substantial acidemia and hypercapnia,
which is also consistent with our results. In that
study by Ho et al., the IAP did not affect metabolic function, acid-base balance or hemodynamics (33). The investigators installed an IAP of
7 and 14mmHg each for 30 minutes to test the
IAP ranges for laparoscopic procedures which elicited splanchnic and pulmonary hemodynamic
and metabolic changes (33). The effect of low IAP
(7mmHg) on splanchnic perfusion was pointed out
to be minimal whereas higher IAPs (14mmHg) decreased the portal and hepatic blood flow, lowered
the hepatic and intestinal tissue pH. In our study,
the IAPs were kept in the range of 11-14mmHg
throughout the operations and we found no statistically significant increase in IMA levels, which
would have indicated ischemia.
In a study evaluating the effects of PP on
mesenteric ischemia-reperfusion injury by measuring intestinal tissue oxygen pressure (PtiO2) and
oxidative damage during laparoscopic and open
colon surgery, the authors found that during laparoscopic surgery, there was a significant decrease
of PtiO2 only when PP was increased to 15mmHg.
Although malondialdehyde (MDA) significantly
increased in both Groups after mesentery traction
and at the end of operation versus baseline levels,
there was no difference between techniques (39).
When the effects of prolonged PP (4 hours) during RARP were investigated, it was found that
MDA concentrations were significantly elevated at
74
IBJU | ISCHEMIA MODIFIED ALBUMIN, ROBOTIC PROSTATECTOMY
various intervals as compared with the pre-insufflation value and also the intra-mucosal pH value decreased significantly after CO2 insufflation
compared with the pre-insufflation values. It was
concluded that prolonged PP in RALP resulted
in decreased splanchnic blood flow and PP itself
produced oxidative stress (40). In our study, PP
lasted 3.5 hours and the difference between preand postoperative IMA values was not statistically
significant. Therefore, no ischemia was detected
by measuring IMA.
Our findings did not reveal any renal injury as there was no significant statistical difference between the preoperative and postoperative
BUN and creatinine values, unlike the study of
Bishara et al., where renal perfusion and function
were decreased by induction of IAP of 14mmHg
(41).
The maintenance of the IAP within 1114mmHg during the RARP operations is necessary in order to avoid the complications of PP.
This safety measure certainly protects the patients
from the adverse effects of high IAP. The restriction of IAP might be considered a limitation for
this clinical study, and the sensitivity of IMA as an
ischemic biomarker can further be tested by designing animal studies where IAP may be increased
to higher levels. Further studies may as well be
performed utilizing novel biomarkers to identify
whether there are any mesenteric compartment
like syndromes during RARP.
Based upon the findings obtained as a result of current study; although patients were kept
in steep (45 degrees) Trendelenburg position during
robotic prostatectomies, IAP between 11-14mmHg
does not cause any hypoxia/ischemia detected by
conventional measurement techniques. Even if there
is a hypoxia, which is out of detection limits, this
cannot be followed by serum IMA levels.
In conclusion, during robotic radical prostatectomies performed under steep Trendelenburg
position and when IAP is maintained in between
11-14mmHg, we did not demonstrate any significant mesenteric-splanchnic ischemia that could be
detected by serum IMA levels.
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_______________________
Correspondence address:
Zehra Serpil Ustalar Ozgen, MD
Kazim Karabekir Pasa cad. Ozgen P.No:10/10
Erenkoy Kadikoy, Istanbul, Turkey
E-mail:
[email protected]
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