A pilot study of ice-slurry application for inducing laparoscopic renal hypothermia

Authors


Brett A. Laven, Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden. e-mail: blaven2@hotmail.com

Abstract

OBJECTIVE

To assess, in a pilot study, the feasibility of delivering a microparticulate ice slurry (MPS) to provide regional hypothermia, as renal cooling during laparoscopic procedures is cumbersome and inefficient.

MATERIALS AND METHODS

An ex vivo preparation was used to simulate the boundary conditions of a kidney. Four pig kidneys were placed onto a thin membrane overlying a constant temperature bath (37 °C) with parenchymal thermocouples. Renal surfaces were coated with MPS and temperatures recorded. In an in vivo pig model we assessed laparoscopic delivery and cooling ability of the MPS under physiological conditions. Kidneys in two pigs were laparoscopically exposed; thermocouple probes were placed throughout the kidney and the hilum was clamped. MPS was delivered through a modified 5-mm laparoscopic suction/irrigation cannula. Cortical and core body temperatures were measured.

RESULTS

In the ex vivo study, the mean (sd) initial temperature was 37.1 (0.4) °C; the mean time to reach 15 °C was 10.3 (2.6) min and the mean nadir temperature was 13.0 (1.5) °C. In vivo, the MPS was delivered with no technical difficulty; the mean renal unit starting temperature and core body temperature were 37.2 °C and 37.0 °C, respectively. The mean (range) time to reach 15 °C was 16.5 (5.5–28.6) min. The mean nadir core body temperature was 34.0 °C.

CONCLUSION

This initial study showed efficient and rapid induction of renal hypothermia using MPS delivered through 5-mm laparoscopic ports, with no technical difficulty. These exploratory pilot findings support further, larger scale, histopathological and renal functional investigations of topical ice slurries as a means of providing renal hypothermia in laparoscopic procedures.

Abbreviations
AAA

abdominal aortic aneurysm

MPS

microparticulate (ice) slurry

WI

warm ischaemia

LPN

laparoscopic partial nephrectomy

INTRODUCTION

The development of refined techniques and more advanced instrumentation has facilitated complex laparoscopic procedures such as partial nephrectomy (LPN), renal revascularization, renal autotransplantation, and the repair of abdominal aortic aneurysm (AAA) [1–7]. These procedures are technically challenging and can require prolonged periods of renal warm ischaemia (WI). During open surgery, renal hypothermia is frequently used to lower the metabolic rate and protect renal function during prolonged ischaemic intervals [3,8–10]. Renal hypothermia permits up to 3 h of ischaemia with no permanent loss of renal function [9,11]. However, currently, there is no efficient and effective method for inducing renal hypothermia laparoscopically.

Renal ischaemia times remain a limiting factor in the ability to laparoscopically manage more complex renal tumours, renovascular disease, and many AAAs [1,2,10,12–14]. Proposed methods of laparoscopic renal hypothermia are often cumbersome, can compromise exposure, and can have limited applications or unconfirmed clinical benefits [12–14]. Efficient renal hypothermia would permit more adequate time for complex laparoscopic procedures that require prolonged renal ischaemia. Therefore, the development of efficient renal cooling techniques remains a focus of laparoscopic research [12–15].

In the present pilot study we evaluated the cooling ability and ease of administration of a laparoscopically delivered microparticulate ice slurry (MPS), which was previously used to provide total-body and targeted brain and heart hypothermia when infused through central venous catheters in a pig model [16–18]. During the present study, both an ex vivo and an in vivo model were developed to assess the potential of MPS for laparoscopic renal cooling and thus support the need for further investigation.

MATERIALS AND METHODS

Two groups (Argonne National Laboratory and the Section of Urology, University of Chicago) collaborated to develop an efficient laparoscopic renal hypothermia technique. The protocol was approved by the Institutional Animal Care and Use Committee at the University of Chicago. The MPS developed by the Argonne National Laboratory is a two-phase fluid slurry comprised of smooth globular ice particles of <100 µm in diameter, suspended in saline (Fig. 1) that was previously investigated for its potential to achieve total body hypothermia [18]. The MPS has sufficient fluidity to be delivered through an 8 F catheter or a 14-G hypodermic needle at very high ice-loading with no obstruction. By contrast, standard ice-slush used for renal hypothermia during open procedures comprises dendritic ice crystals, which are elongated, rough, and entangle to form large clusters that will not flow, even at moderate ice-particle loading values, without plugging delivery tubing (Fig. 1).

Figure 1.

MPS (left, top and bottom) is composed of smooth globular (100 µm) ice particles with superior fluid dynamic properties that make it suitable for pumping through i.v. catheters, hypodermic needles or other medical delivery tubing. Dendritic ice (right, top and bottom), as produced by conventional slush machines, cannot be readily pumped, and produces plugging when poured.

The cooling efficiency of the MPS was first evaluated using an ex vivo preparation designed to simulate a kidney during vascular clamping. After laparoscopic nephrectomy, four pig kidneys were removed and placed on a membrane stretched across a constant temperature bath at 37 °C (Fig. 2). This design was used to simulate a physiological setting, in which the kidney is in thermal contact with the body wall. Eight thermocouples were then inserted at uniform locations throughout the renal parenchyma to a depth of 1 cm. Exposed parenchymal surfaces were coated with MPS and serial temperatures were recorded until a constant temperature of ≤ 15 °C was maintained for 5 min.

Figure 2.

A pig kidney with thermocouples on a membrane overlying a constant 37 °C bath with topical MPS delivery.

After assessing the ex vivo preparation, an in vivo model was developed, using two female farm pigs. The laparoscopic procedure was performed transperitoneally. The peritoneum was incised and the colon reflected medially to expose the hilar vessels. The renal artery and vein were dissected, with care taken to ensure that there were no collateral or aberrant vessels that required clamping. Eight thermocouple probes were inserted to a depth of 1 cm at eight evenly distributed locations throughout the kidney, i.e. one upper, two mid, and one lower pole probe on both the anterior and posterior surfaces of the kidney. Core body temperature was measured throughout the procedure using a nasal temperature probe.

After measuring the baseline core body temperature, laparoscopic bulldog clamps (Aesculap, Center Valley, PA, USA) were individually placed on both the artery and vein. Core body temperature was again recorded, after which the MPS was introduced, uniformly covering the kidney. The MPS was delivered through vinyl tubing using a peristaltic pump and a modified 5-mm laparoscopic suction/irrigation cannula inserted through a 5-mm port (Fig. 3). The MPS that melted was continuously replaced to maintain regional hypothermia. MPS administration was continued until all thermal probes indicated a temperature of ≤ 15 °C maintained for 5 min.

Figure 3.

Laparoscopic delivery of MPS to the kidney surface using a modified 5 mm laparoscopic suction cannula with transcutaneous thermocouple instrumentation: (A) abdominal wall; (B) bowel; (M) MPS.

This procedure was subsequently used in one of the pigs, using open renal exposure to serve as a control and to confirm the renal cooling ability of the MPS. A flank incision was made and dissection carried out until hilar control was achieved. Hilar clamping was done using bulldog clamps and the renal temperature monitored using thermal probes, as described previously.

RESULTS

In the ex vivo system the kidneys were successfully coated with a layer of MPS at a rate of 200 mL/min. The mean (sd) start temperature was 37.1 (0.4) °C. The mean (range) time to reach a temperature of 15 °C was 10.3 (7.7–12.9) min. The mean nadir temperature was 13.0 (1.5) °C. The MPS maintained good contact with the kidney surface and could be selectively removed from portions of the kidney surface after inducing hypothermia. The particles did not freeze together or cluster during delivery.

In the in vivo model with laparoscopic delivery, the MPS was delivered at a rate of 200 mL/min with no technical difficulty. The mean starting temperature of the renal units was 37.2 (0.5) °C. There was no significant temperature difference between the baseline measurements from anterior and posterior locations, or when comparing upper-, mid- and lower-pole locations. The mean time to achieve a temperature of 15 °C was 16.5  (5.5–28.6) min. The mean starting core body temperature was 37.0 °C. The mean core body temperature at the time of unclamping and mean nadir core body temperature were 34.9 °C and 34.0 °C, respectively.

During MPS delivery, the slurry flowed easily through the 5-mm cannula and there was no plugging. Throughout the procedure, the MPS maintained good contact with the kidney surface and could be selectively removed from portions of the kidney surface. The slurry formed a mould on the kidney surface, which was malleable, and could be easily sculpted with the tip of the suction cannula or a Kitner dissector.

In the in vivo model we also used open application of MPS on the contralateral renal unit after the initial laparoscopic cooling experiment. The mean (range) renal unit starting (thermocouple) temperature was 33.2 (32.9–33.6) °C, and the mean time to achieve a temperature of 15 °C in all thermal probes was 18.9 (15.5–28.0) min. After showing effective cooling via an open approach, the procedure was terminated.

DISCUSSION

The adverse effects of prolonged WI on renal function are well documented [10,19–21]. Retrospective laparoscopic series have described tolerance to WI times of >30 min, but used serum creatinine to assess overall renal function in patients with a normal contralateral kidney [3,22]. Consequently there are no specific data on the kidney sustaining the ischaemic insult. While recent investigations showed that the kidney can fully recover from WI times up to 90 min in a solitary-kidney porcine model, the responses to renal injury in the pig are not directly analogous to human pathophysiology [23]. Renal WI time remains the most critical factor in determining renal function after procedures requiring interruption of renal blood flow [20,21]. Thus renal ischaemia is of utmost importance during partial nephrectomy, AAA repair with suprarenal cross-clamping, aortorenal bypass, and renal autotransplantation [1–3,8,10,19,24].

Renal cooling is recommended when ischaemic intervals are anticipated to last >30 min, such as complex vascular anastomoses, resection of large or complex renal masses, and renal tumours at unfavourable sites [3,8–10]. During open procedures, renal hypothermia is established using topical hand-packed ice slush or chilled intravascular instillations [3,8–10]. However, standard ice-slush will not flow efficiently through small-calibre laparoscopic cannulae [18]. Ice-particle agglomeration and clustering cause plugging of even larger calibre, 10-mm, laparoscopic cannulae. Intravascular cooling and other hypothermia techniques can be inefficient, can compromise operative exposure, and still have unconfirmed clinical benefit [12–14]. In an effort to decrease morbidity and improve patient outcomes, partial nephrectomy, AAA repair and renovascular procedures have begun to be managed laparoscopically, but these procedures are nearly always performed under WI conditions with the inherent risk of ischaemic renal damage [1–7]. Currently, the inability to efficiently establish laparoscopic renal hypothermia has limited the laparoscopic management of more complicated renal tumours and renovascular diseases [1,2,12–14]. Thus efficient renal cooling techniques remain a focus of laparoscopic renal surgery research [12–15].

LPN provides comparable tumour control with less morbidity than open procedures [25]. During laparoscopic nephron-sparing surgery there is an emphasis on duplicating the established principles of open oncological surgery [3,12,14,22]. In the case of LPN, these principles include vascular control, precise tumour resection, and use of hypothermia when resection times are anticipated to be >30 min [9]. In an effort to limit renal ischaemia during LPN, compressive devices and novel energy sources have been used to eliminate or minimize the need for full vascular control [26,27]. These techniques do not duplicate the principles of open surgery and have largely been abandoned. Refinements in technique and advances in instrumentation have been introduced to help minimize renal WI time [3,22,28]. However, tumour resection, collecting system repair, and control of parenchymal vessels remains a technically demanding task in 30 min of WI time [22,29]. Consequently, LPN has remained predominantly limited to smaller, exophytic, favourably located lesions to limit WI time [3,12,13].

Proposed renal hypothermia techniques for partial nephrectomy include intravascular, topical, and intra-ureteric cooling. Janeteschek et al.[12] perfused iced Ringers’ lactate through a pre-placed femoral angiocatheter advanced to the level of the renal artery. This might be more difficult when there are multiple renal arteries and in patients with atherosclerotic disease [13]. Intravascular cooling also requires careful monitoring of i.v. fluid administration due to the risk of associated fluid overload [12]. This technique is not applicable in juxtarenal aortic aneurysm repair, renovascular surgery, or renal autotransplantation. Costs are also increased by the need for an interventional radiologist and extra time is needed for placing the angiocatheter. Landman et al.[14] instilled cold saline into the renal pelvis through a pre-placed ureteric access catheter. The technique was effective, but nadir parenchymal temperatures did not approximate topical ice-slush techniques. Further, in the event of collecting system violation during resection, irrigant spillage might compromise cooling efficiency and visualization.

Topical renal hypothermia was investigated by Gill et al.[13], who injected conventional ice slush into an Endocatch bag exteriorized at a 12-mm port site through modified 30 mL syringes. This technique achieved nadir renal parenchymal temperatures of 5–19 °C and closely approximated the established techniques of open PN. However, it requires removal and changing of ports, enlargement of port-site incisions, and incision and mobilization of the Endocatch bag to allow tumour resection. In addition, the investigators noted that the bag might compromise operative exposure, and in one case interfered with a hilar clamp, causing additional blood loss. The authors also commented that space limitations prevent the use of this technique in retroperitoneoscopic procedures. Recently, Ames et al.[15] investigated an ice slurry that can be topically applied to the kidney. There was efficient cooling but the slurry required a custom-built 10-mm delivery device to prevent plugging from ice-crystal agglomeration characteristic of dendritic ice-slush mixtures. The fluid properties of the MPS used in the present study allow it to be easily delivered through 5-mm cannulae with no plugging.

Both topical and intravascular renal hypothermia have been investigated in laparoscopic renal revascularization. Gentileschi et al.[2] assessed the feasibility of laparoscopic aortorenal bypass in a pilot study in the pig. The median ischaemia time during aorta-to-graft and graft-to-renal artery anastomoses was 65 and 50 min, respectively. These investigators placed an ice-containing bag on the anterior kidney surface during suprarenal cross-clamping. In another pilot study of laparoscopic aortorenal bypass, intravascular hypothermia was used by perfusing 300 mL of iced heparinized saline into the renal artery [5]. The mean renal ischaemia time was 61 min. These investigators were only able to perfuse the renal artery during the aorta-to-graft anastomosis and thus no cooled heparin was infused while the renal artery was anastomosed to the graft. Both of these studies concluded that laparoscopic aortorenal bypass is feasible, but that renal ischaemia time was not yet optimal, and further refinements in technique and instrumentation were necessary to make the procedure more efficient.

In the present initial study, we describe a method of delivering a novel ice-slush, which mirrors open surgery techniques, to provide renal hypothermia during laparoscopic procedures [9]. It was successful in a transperitoneal approach and might potentially be used in retroperitoneoscopic procedures. The MPS is delivered through a modified 5-mm laparoscopic cannula and thus does not require larger ports, additional procedures, or repositioning. The slurry is easily applied to the outer surface of the kidney forming a mould-like shell around it, providing highly efficient and rapid renal cooling. The particles do not completely freeze together and thus the slurry mould is malleable, with a consistency that easily allows it to be sculpted with a suction cannula or Kitner dissector to facilitate tumour resection. This prevents a generalized ‘pooling’ of slurry around the peritoneal cavity, which can contact bowel and adjacent viscera.

The present study was a pilot and thus serves only to assess the feasibility of using an ice slurry to provide renal hypothermia. As in any pilot study, there are limitations to the initial data, which need to be addressed in future investigations. Long-term animal studies to assess the safety and efficacy of this cooling method are necessary. Studies must be designed to investigate the renal parenchyma and adjacent viscera to assess for histopathological evidence of hypothermic tissue trauma. To ultimately confirm the efficacy of the ice slurry, renal function must be assessed after cold ischaemic intervals. Finally, laparoscopic procedures such as LPN and renal revascularization should be done using the slurry in an animal model. Nevertheless, while there are limitations to this pilot study, we think that using MPS is a promising technique of cooling the kidney during laparoscopic procedures, and hope that this initial report will stimulate other investigations into topical laparoscopic renal hypothermia.

In conclusion, we describe the feasibility of a simple, efficient, and reproducible technique of achieving laparoscopic renal hypothermia using a novel ice slurry. The present results support further, large-scale, investigations of MPS. Efficient renal hypothermia would facilitate more complex LPN and renovascular procedures that require prolonged renal ischaemia. While the cooling efficiency and ease of use associated with the MPS make it a promising tool, further studies are mandatory before clinical use of MPS can be considered.

CONFLICT OF INTEREST

B. Laven, K. Kasza, M. Orvieto, J. Oras, D. Beiser, T. Vanden Hoek, H. Son and A. Shalhav are all patent holders/inventors for the mentioned product. K. Kasza and T. Vanden Hoek are also founders of Cold Core Therapeutics Inc. Source of funding: NIH-Bioengineering Research Partnership Grant, University of Chicago, DUDA Fund.

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