Laparoscopy involves insufflation of the abdomen with CO2 to create a working space that allows for maneuvering of an endoscope and instruments.1 Laparoscopic procedures in dogs cause less surgical stress and postoperative pain and improve postoperative recovery, compared with traditional open approaches.2–4 Because of these benefits, laparoscopy is commonly performed in veterinary medicine.5,6
Insufflation with STCO2 for laparoscopy is performed at a temperature of 22°C and 0% relative humidity.7–9 Core body temperature of dogs ranges from 37.5° to 39.2°C,10 which is ≥ 15°C higher than that of the insufflated CO2. The use of STCO2 insufflation is a major cause of hypothermia in human patients undergoing laparoscopic procedures, which is the result of heat loss attributable to evaporation of liquid from the peritoneal surface at a rate of decrease of 0.3°C in core body temperature for every 50 L of insufflated CO2.9 Effects of the use of STCO2 on core body temperature in dogs are unknown.
Perioperative hypothermia in dogs is defined as a body temperature < 36.5°C.11 Perioperative hypothermia has detrimental effects that can lead to patient morbidity, including cardiac, hepatic, and renal dysfunction; coagulopathies; increases in transfusion requirements; impairments of humoral and cellular immunity that affect wound healing; prolongation of recovery; and alterations of drug metabolism.11,12 Inadvertent perianesthetic hypothermia is one of the most common complications associated with anesthesia.12 In 1 study11 of approximately 1,500 dogs undergoing general anesthesia for surgical or diagnostic procedures, 84% were classified as hypothermic at the time of anesthetic recovery.
Investigation of the hemostatic effects of hypothermia in humans revealed hypocoagulability in clinical patients and impairment of in vitro hemostasis (as measured with thromboelastography).13 Even mild perioperative hypothermia (decrease in core body temperature of 1° to 3°C) resulted in increased bleeding times during surgery, higher rates of blood loss, and an increased need for blood transfusion in people undergoing surgery.14 Similar to results for humans, intraoperative hemorrhage may be exacerbated by perioperative hypothermia in dogs, which can lead to complications such as the need for a blood transfusion, hypoxia, and even death.15
Strategies to prevent perioperative hypothermia are needed to ensure safe outcomes for patients undergoing laparoscopy. Use of WHCO2 (37°C and 97% relative humidity) for creation of pneumoperitoneum has been evaluated extensively for laparoscopic surgery in humans through evaluation of core body temperature, postoperative pain, recovery time, postoperative nausea, urine output, lens fogging, and hemodynamic data.16–21 In 50 morbidly obese patients undergoing gastric bypass surgery, use of WHCO2 resulted in a higher intraoperative core body temperature and less postoperative shivering, compared with results for use of STCO2.17 In contrast, clinical trials of adult humans found no differences in intraoperative core body temperature between CO2 treatments.18,19,21 A study20 of pigs (body weight, 30 to 35 kg) to compare insufflation devices found that WHCO2 used for pneumoperitoneum and duration of the procedure impacted heat loss, with heat loss for WHCO2 being significantly less than that for STCO2 only at ≥ 50 minutes. Variation in the peritoneal surface area in dogs, compared with that in humans,22 may allow thermoregulatory protection for dogs when WHCO2 is used.
Apart from the potential thermoregulatory benefits, WHCO2 creates a less irritant environment, which results in reduced patient discomfort in humans.17,21,23,24 Studies23,24 of rats have revealed that insufflation with WHCO2 during laparoscopy reduces peritoneal injury and adhesion formation as detected with scanning electron microscopy. It is the preservation of peritoneal tissues from desiccation that is thought to mediate a reduction in the systemic inflammatory response as indicated by a reduction in the concentrations of circulating CRP and IL-6.a Both CRP and IL-6 are inflammatory mediators used as biomarkers to assess the presence and degree of tissue damage. These substances are sensitive indicators of surgical trauma and inflammation in dogs.25
Advanced laparoscopic procedures (eg, cholecystectomy, ureteronephrectomy, and adrenalectomy) are being performed in veterinary medicine, which requires prolonged periods of pneumoperitoneum. However, to our knowledge, the effects of WHCO2 in dogs undergoing laparoscopy have not been investigated. Evaluation of the use of WHCO2 is necessary to optimize postoperative recovery and outcome.
The objective of the study reported here was to evaluate the effect of insufflation with WHCO2 to create pneumoperitoneum on cardiorespiratory variables, core body temperature, the systemic inflammatory response, coagulation, peritoneal morphology, and signs of postoperative pain in healthy mature dogs undergoing laparoscopy. Our hypothesis was that the use of WHCO2 would result in better thermoregulation, a reduced inflammatory response, better cardiovascular function, and signs of less pain than for the use of STCO2.
Materials and Methods
Animals
Six healthy mature (> 6 years old) purpose-bred Beagles were used in the study. Body weight ranged between 9.6 and 13.7 kg. All dogs had body condition scores within acceptable limits (4 to 6; scale of 1 to 9). A CBC, biochemical analysis, and physical examination were performed on each dog prior to enrollment in the study; results were within acceptable limits.
All procedures were performed in the comparative clinical research facility at the University of Guelph Ontario Veterinary College and were conducted in accordance with the animal use protocol of the University of Guelph. All dogs were housed in the Central Animal Facilities at the University of Guelph and cared for in compliance with the Canadian Council on Animal Care guidelines and the Animals for Research Act.
Experimental design
Dogs were allowed an acclimatization period of 7 days prior to laparoscopy. A crossover study was conducted. Dogs were randomly assigned by use of a random number generatorb to initially receive STCO2 (22°C and 0% relative humidity) or WHCO2 (37°C and 98% relative humidity) for creation of pneumoperitoneum during laparoscopy. Laparoscopy was repeated, and dogs received the other CO2 treatment to create the pneumoperitoneum. There was a washout period of at least 3 weeks between the 2 laparoscopic procedures.
Anesthesia and instrumentation
Food was withheld from dogs for 12 hours before anesthesia. On the day of surgery, a 20-gauge, 1.88-inch catheterc was placed in a cephalic vein of each dog. Dogs were premedicated with hydromorphoned (0.05 mg/kg, IV) before anesthetic induction with propofole (2 to 4 mg/kg, IV). Dogs were intubated, and anesthesia was maintained with isofluranef (ETISO, 1.6%), which was measured with an infrared gas analyzerg that had been calibrated before each experiment with the recommended standardized calibration gas mixture.h Dogs were also instrumented for electrocardiography and measurement of HR, CVP, direct arterial pressures (SAP, DAP, and MAP), esophageal temperature, Petco2, and specific spirometry variables (tidal volume, respiratory rate, and peak inspiratory pressure) by use of a multiparameter monitor.g Intermittent positive-pressure mechanical ventilation was initiated with a volume-cycled ventilatori to maintain an initial Petco2 of 40 mm Hg. Subsequent Petco2 values during the experiment were recorded without adjusting ventilator settings. Standard practices for maintaining core body temperature of dogs were applied, including use of a warming water blanket and warmed air.j Room temperature and relative humidity were measured with a thermohygrometerk at all time points. Intravascular volume support was provided throughout the procedure by IV administration of an isotonic balanced solutionl (rate, 3 to 5 mL/kg/h) that was at room temperature (21°C).
An 18-gauge double-lumen catheterm was placed in the left jugular vein and a 20-gauge, 1-inch catheter was placed in a dorsal pedal artery for collection of central venous and arterial blood samples, respectively, for measurement of pH, blood gas tensions, and central venous and arterial oxygen saturation, lactate concentration, electrolyte concentrations, and hemoglobin content. Cardiac output was determined by use of the LiDCOn method by attaching a lithium chloride sensoro to the side port of a 3-way valve connected to the arterial catheter. Extension tubing was attached to the 3-way valve and connected to a blood collection bag, and blood passed through a peristaltic pump that produced a blood flow of 4 mL/min across the sensor. The hemoglobin concentration and serum sodium concentration required by the LiDCO computer were determined before the cardiac output measurement by use of a blood gas analyzer.p A dose of lithium chlorideq (0.006 mmol/kg) was injected into an extension set attached to the jugular vein catheter, which was flushed with 8 mL of saline (0.9% NaCl) solution 8 seconds after the injection phase was started.
Each dog was positioned in dorsal recumbency, and a standard 3-step aseptic preparation of the ventral surface of the abdomen was performed. A 0.5-cm incision was made caudal to the umbilicus; the skin, subcutaneous tissues, and linea alba were incised to allow placement of the camera portal by use of a standard 6-mm laparoscopic cannular with a Hasson technique. A purse-string suture was placed around the cannula to minimize leakage of CO2. Standard insufflation tubing or specialized tubing connected to a device,s which was designed to warm insufflated CO2 via a heated coil, was attached to a mechanical insufflator.t This warmed CO2 passed through the insufflation tubing toward the patient and was humidified during passage through a chamber of sterile water prior to entry into the abdomen. Pneumoperitoneum (intra-abdominal pressure, 10 mm Hg) was induced with CO2 injected by the mechanical insufflator. The volume of CO2 used was recorded for each dog. A laparoscopeu (0°; 5 mm × 29 cm) was inserted into the abdomen through the camera portal, and visible abdominal organs were briefly evaluated. Laparoscopic guidance was used to create an instrument portal halfway between the camera portal and pubis; the instrument portal was used for placement of the 6-mm laparoscopic cannula.
Cardiorespiratory measurements
Cardiorespiratory variables and core body temperature were measured in each dog before (time 0; baseline) and 5, 15, 30, 45, 60, and 90 minutes after initiation of pneumoperitoneum with CO2 and 5 minutes after desufflation. Cardiac output, SAP, DAP, MAP, HR, CVP, arterial oxygen saturation, central venous oxygen saturation, arterial and central venous blood gas tensions, spirometry variables, electrolyte concentrations, lactate concentration, ETISO, and Petco2 were recorded. Cardiac index, SV, SVI, SVR, Cao2, Ccvo2, 
o2, Do2, and oxygen extraction ratio were calculated.26,27 The dose of propofol required for induction, interval from induction to initiation of pneumoperitoneum, and duration of surgery and anesthesia were recorded.
Evaluation of tissue and blood samples
A blood sample (3 mL) was collected into a tube containing citrate as an anticoagulant at baseline, immediately after completion of laparoscopy, and 24 and 48 hours after completion of laparoscopy. The sample was used for determination of packed RBC volume and total protein concentration. In addition, global hemostasis was evaluated by use of kaolin-activated thromboelastography.v An aliquot (1 mL) of citrated blood was pipetted into a kaolin-containing vialw and gently inverted 5 times. Thromboelastography was performed with 340 μL of kaolin-activated blood; the blood was pipetted into a reaction cup, and 20 μL of 0.2M CaCl2 was added. Measurements were performed at the standard machine temperature of 37°C. Reference ranges for the variables were specific for the Ontario Veterinary College and based on previous data. Reaction time was the time until a clot was first detected (reference range, 2 to 7 minutes). The MA (reference range, 47 to 68 mm) and G (reference range, 4.5 to 8.5 dynes/s) were used as measures of clot strength and indicated platelet function and fibrinogen concentrations. The coagulation index (reference range, −3 to 3) was used as an overall assessment of coagulability by taking into account the relative contribution of all thromboelastography measurements.28 Blood samples were collected from the catheter in the left jugular vein into plain serum tubes at baseline and 1, 4, 12, 24, and 48 hours after initiation of pneumoperitoneum and used to measure CRP and IL-6 concentrations.
A peritoneal biopsy specimen was collected 5, 30, and 90 minutes after initiation of pneumoperitoneum by use of 5-mm laparoscopic cup biopsy forcepsx introduced through the instrument portal; specimens were submitted for scanning electron microscopy. The first biopsy specimen was collected from the right lateral abdominal wall just caudal to the last rib at a location approximately 10 cm dorsal to the ventral midline. Each subsequent biopsy specimen was collected 2 to 5 cm caudal to the location of the preceding sample. For the second laparoscopic procedure, biopsy specimens were collected from the left lateral abdominal wall in a similar manner. Tissues were fixed by incubation in a mixture of 2.5% glutaraldehyde in 0.1M PBS solution (pH, 7.3) for 1 to 2 weeks at room temperature. Samples were washed in 0.1M PBS solution (pH, 7.4) for 30 minutes before postfixation by incubation in a mixture of 1% osmium tetroxide in 0.1M PBS solution for 2 hours. Samples were then dehydrated in an ascending series of ethanol solutions (50%, 75%, 95%, and 100% ethanol) for 15 minutes and dried with a critical point dryer. Samples were sputter coatedy with a gold-palladium mixture prior to examination by use of a scanning electron microscopez at an accelerating voltage of 10 kV. Electron micrographs were obtained and reviewed by a board-certified veterinary pathologist (RAF). The degree of peritoneal desiccation and desquamation were subjectively scored. A scoring system designed by 2 of the authors (JES and RAF) was used to assign each variable a value between 0 and 4 as follows: 0 = skeletal muscle present but no mesothelial cells, 1 = serosal connective tissue present but no mesothelial cells, 2 = serosal connective tissue present but few mesothelial cells, 3 = serosal connective tissue present and an intermediate number of mesothelial cells, and 4 = serosal connective tissue present and normal mesothelium.
Recovery and pain score
At the end of each laparoscopic procedure, all instruments were removed, and the pneumoperitoneum was purged. Portal sites were locally infiltrated with lidocaineaa (2 mg/kg), and incisions were closed in a routine manner. Anti-inflammatory medication was provided (meloxicambb; 0.1 mg/kg, IV), and dogs were allowed to recover from anesthesia.
An investigator (JJK) who was unaware of the treatment for each dog evaluated recovery from anesthesia and signs of postoperative pain by use of the short-form Glasgow Composite Pain Scale.29 All dogs were monitored continuously immediately after the end of anesthesia until they were able to stand; dogs then were assessed at 4, 12, 24, and 48 hours after surgery for signs of pain. A score ≥ 6 was considered justification for the provision of rescue analgesia with hydromorphone (0.05 mg/kg, IM). Dogs were returned to the research facility 48 hours after laparoscopy.
Data analysis
Comparisons of core temperature, cardiorespiratory and thromboelastography variables, and inflammatory biomarkers between treatments for each dog were performed with a generalized linear mixed modelcc with a random effect by use of a 3-factor design with repeated measurements for each dog; the 3 factors were treatment, time, and sex. Data were assessed for normality with a Shapiro-Wilk test. Backward stepwise regression was performed, and Tukey and Dunnett corrections were made for pairwise comparisons. Significance was set at P ≤ 0.05. Normally distributed data were summarized as mean and 95% CI. Data that were not normally distributed underwent logistic regression and were summarized as median and range and OR. Because of the scarcity of data for values > 0 for postoperative pain score, this outcome was dichotomized to reflect a score of 0 or > 0.
A limited number of tissue samples were processed because of financial and time constraints. Therefore, statistical analysis for peritoneal morphology observed with scanning electron microscopy was not performed.
Results
The dogs comprised 4 spayed females and 2 castrated males with a median age of 7.5 years (range, 6.4 to 10.3 years) and a median body weight of 11 kg (range, 9.6 to 13.7 kg). Body weight did not differ significantly (P = 0.095) between males and females.
Dose of propofol used for induction did not differ significantly (P = 0.117) between treatments (STCO2: mean, 2.2 mL [95% CI, 1.5 to 2.9 mL]; WHCO2: mean, 2.6 mL [95% CI, 1.9 to 3.3 mL]). The ETISO did not differ significantly (P = 0.189) between treatments (STCO2: median, 1.75% [range, 1.66% to 1.83%]; WHCO2: median, 1.71% [range, 1.64% to 1.80%]). Interval from induction to baseline measurement did not differ significantly (P = 0.184), between treatments (STCO2: mean, 48 minutes [95% CI, 37 to 58 minutes]; WHCO2: mean, 52 minutes [95% CI, 42 to 63 minutes). Duration of surgery time did not differ significantly (P = 0.128) between treatments (STCO2: mean, 107 minutes [95% CI, 102 to 112 minutes]; WHCO2: mean, 111 minutes [95% CI, 107 to 116 minutes]). Finally, duration of anesthesia did not differ significantly (P = 0.204) between treatments (STCO2: mean, 173 minutes [95% CI, 160 to 187 minutes]; WHCO2: mean, 181 minutes [95% CI, 167 to 194 minutes]).
Mean core body temperature was significantly (P < 0.001) lower across time for the WHCO2 treatment (mean, 35.2°C; 95% CI, 34.5° to 35.8°C), compared with values for the STCO2 treatment (mean, 35.9°C; 95% CI, 35.3° to 36.6°C), despite the fact room temperature (P = 0.378) and relative humidity (P = 0.451) did not differ significantly between treatments. All dogs were classified as hypothermic (< 36.5°C) for the first 60 minutes of the laparoscopic procedures; however, core body temperature increased significantly (P < 0.001) in all dogs after the first 30 minutes of pneumoperitoneum, compared with the baseline value.
The HR (P = 0.656), cardiac output (P = 0.273), cardiac index (P = 0.873), SVI (P = 0.947), Do2 (P = 0.790), oxygen extraction ratio (P = 0.240), CVP (P = 0.481), SVR (P = 0.619), Cao2 (P = 0.167), and Ccvo2 (P = 0.065) did not differ significantly between treatments (Table 1). However, HR increased significantly (P < 0.001) during the laparoscopic procedure (Figure 1). There was a significant (P = 0.027) sex-by-time interaction because male dogs had a higher HR earlier in the procedure then did female dogs.
Mean HR of 6 healthy mature dogs (4 females [inverted triangles] and 2 males [diamonds]) undergoing laparoscopy by use of insufflation with STCO2 or WHCO2. There was a washout period of 3 weeks between laparoscopic procedures. Time 0 was immediately before the initiation of pneumoperitoneum. The HR increased significantly (P < 0.001) during the laparoscopic procedure, and there was a significant (P = 0.027) sex-by-time interaction because male dogs had a higher HR earlier in the procedure then did female dogs.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
Mean (95% CI) or median (range) values for cardiovascular variables in 6 healthy mature dogs undergoing laparoscopy with pneumoperitoneum induced by insufflation with STCO2 or WHCO2.
| Time (min) | HR (beat/min; mean [95% CI]) | Cardiac index (mL/min/kg; median [range]) | SVI (mL/beat/kg; mean [95% CI]) | Do2 (mL/min; median [range]) | Oxygen extraction ratio (%; mean [95% CI]) |
|---|---|---|---|---|---|
| 0 | 104 (84–125) | 112 (92–137) | 1.1 (1.0–1.3) | 22.3 (17.5–28.5) | 6.2 (3.3–9.1) |
| 5 | 114 (97–131) | 152 (125–185)* | 1.4 (1.2–1.6) | 30.6 (24.0–39.1)* | 10.7 (7.8–13.6)* |
| 30 | 122 (106–138) | 165 (135–201)* | 1.4 (1.3–1.6)* | 31.4 (24.6–40.1)* | 10.1 (7.3–13.0)* |
| 60 | 138 (122–154)* | 159 (131–194)* | 1.2 (1.0–1.4) | 29.9 (23.4–38.2)* | 12.7 (9.8–15.6)* |
| 90 | 145 (128–161)* | 168 (138–205)* | 1.2 (1.0–1.4) | 31.5 (24.7–40.3)* | 10.4 (7.7–13.4)* |
Laparoscopy was performed twice on each dog; there was a washout period of at least 3 weeks between the 2 procedures. Time 0 was immediately before initiation of pneumoperitoneum.
Value differs significantly (P ≤ 0.05) from the value at time 0.
Cardiac output and cardiac index increased significantly (P < 0.001) from baseline after induction of pneumoperitoneum (Table 1). There was a significant sex-by-treatment interaction for cardiac output (P = 0.023) but not for cardiac index (P = 0.054). The interaction was associated with a nonsignificant (Tukey-adjusted P = 0.161) increase in cardiac output between treatments for male dogs (Figure 2).
Median cardiac output for 6 dogs (4 females and 2 males) undergoing laparoscopy by use of insufflation with STCO2 (circles) or WHCO2 (squares). There was a significant (P = 0.023) sex-by-treatment interaction because male dogs had a higher median cardiac output with STCO2 insufflation than with WHCO2 insufflation.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
The SVI increased significantly (P = 0.003) from the baseline value during the first 30 minutes of the laparoscopic procedure (Table 1). The SVR differed significantly (P = 0.009) over time (Figure 3). There was a significant (P = 0.047) sex-by-treatment interaction for SVR.
Mean and 95% CI values for SVR for 6 dogs (A) and mean SVR for those dogs (4 females and 2 males) when undergoing laparoscopy by use of insufflation with STCO2 (circles) and WHCO2 (squares; B). In panel A, there was a significant difference in mean SVR over time (P = 0.009). In panel B, there was a significant (P = 0.047) sex-by-treatment interaction.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
Mean CVP increased significantly (P < 0.001) from the baseline value (9 mm Hg; 95% CI, 6 to 12 mm Hg) after induction of pneumoperitoneum (13 mm Hg; 95% CI, 10 to 17 mm Hg) and remained elevated for the first 30 minutes of the laparoscopic procedure. There was a significant (P < 0.001) sex-by-treatment interaction, with a higher CVP recorded for male dogs with pneumoperitoneum induced by use of STCO2 (mean, 12 mm Hg; 95% CI, 8 to 17 mm Hg) than when pneumoperitoneum was induced by use of WHCO2 (mean, 9 mm Hg; 96% CI, 5 to 14 mm Hg). Inversely, a lower CVP was recorded for female dogs when pneumoperitoneum was induced with STCO2 (mean, 9 mm Hg; 95% CI, 6 to 13 mm Hg) than when pneumoperitoneum was induced with WHCO2 (mean, 12 mm Hg; 95% CI, 8 to 15 mm Hg).
Both Cao2 (P = 0.032) and Ccvo2 (P = 0.007) decreased significantly during the laparoscopic procedure for both treatments. However, Do2 and the oxygen extraction ratio increased significantly (P < 0.001) after induction of pneumoperitoneum and remained elevated for the duration of the procedure for both treatments (Table 1). Similarly, o2 increased significantly (P < 0.001) after induction of pneumoperitoneum and remained elevated for the duration of the procedure for both treatments (Table 2). When pneumoperitoneum was induced by the use of WHCO2, dogs had a significantly (P = 0.040) lower median o2 rate (2.4 mL/min; range, 1.9 to 3.1 mL/min) than when pneumoperitoneum was induced by the use of STCO2 (2.8 mL/min; range, 2.2 to 3.5 mL/min) at all time points.
Median (range) values for Vo2 in 6 healthy mature dogs undergoing laparoscopy with pneumoperitoneum induced by insufflation with STCO2 or WHCO2.
| o2 (mL/min) | ||
|---|---|---|
| Time (min) | STCO2 | WHCO2 |
| 0 | 1.36 (1.09–1.70) | 1.19 (0.84–1.69)* |
| 5 | 3.06 (2.45–3.81)† | 2.67 (1.88–3.78)*† |
| 30 | 3.25 (2.61–4.05) | 2.84 (2.00–4.02)* |
| 60 | 3.80 (3.05–4.73)† | 3.31 (2.34–4.70)*† |
| 90 | 3.29 (2.64–4.10)† | 2.87 (2.03–4.07)*† |
Value differs significantly (P ≤ 0.05) from the value for STCO2.
Value differs significantly (P ≤ 0.05) from the value at time 0.
See Table 1 for remainder of key.
Mean SAP, DAP, and MAP increased significantly (P < 0.001) from the baseline value after induction of pneumoperitoneum. Mean MAP (P = 0.006) and DAP (P = 0.040) were significantly higher at all time points when pneumoperitoneum was inducted with STCO2. A sex-by-treatment interaction was evident across time for MAP (P = 0.029) and DAP (P = 0.039), with a more persistent arterial blood pressure elevation above the baseline value for female dogs at > 15 minutes after initiation of pneumoperitoneum (Figure 4).
Mean MAP for 6 dogs (4 females [white symbols] and 2 males [black symbols]) undergoing laparoscopy by use of insufflation with STCO2 (circles) or WHCO2 (squares). Mean MAP was significantly (P = 0.006) higher across all time points for STCO2 insufflation, compared with MAP for WHCO2 insufflation. There was a significant (P = 0.029) sex-by-time interaction, with MAP higher than the value at time 0 when pneumoperitoneum duration was > 15 minutes.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
Tidal volume (P = 0.745), Petco2 (P = 0.761), and total volume of CO2 used for insufflation (P = 0.619) did not differ significantly between treatments. Mean Paco2 initially decreased significantly (P = 0.003) after induction of pneumoperitoneum (from 56 mm Hg [95% CI, 52 to 60 mm Hg] to 49 mm Hg [95% CI, 46 to 53 mm Hg), but it returned to baseline values after 15 minutes; this change was not significantly (P = 0.468) different between treatments. However, there was a significant (P < 0.001) effect of sex (Figure 5). There was a significant (P < 0.001) initial decrease in Paco2 in female dogs during the first 5 minutes, which was followed by a steady increase in Paco2. In contrast, male dogs had limited variation in Paco2 throughout the laparoscopic procedure.
Mean Paco2 for 6 dogs (4 females [inverted triangles] and 2 males [diamonds]) undergoing laparoscopy by use of insufflation with STCO2 or WHCO2. There was a significant (P < 0.001) sex-by-time interaction, with Paco2 decreasing in female dogs within the first 5 minutes of the procedure.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
No significant (P = 0.369) treatment effect was evident for mean venous pH. However, there was a significant (P < 0.001) effect of time, with an initial spike in venous pH at the initiation of pneumoperitoneum followed by a gradual decrease in venous pH over time. A similar pattern was evident for mean arterial pH (Figure 6).
Mean arterial pH in 6 dogs (4 females [white symbols] and 2 males [black symbols]) undergoing laparoscopy by use of insufflation with STCO2 (circles) or WHCO2 (squares). Mean arterial pH increased significantly (P < 0.001) after induction of pneumoperitoneum, which was followed by a gradual decrease over the remainder of the procedure. There was a significant (P < 0.001) sex-by-treatment interaction.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
Mean venous lactate concentration increased significantly (P = 0.003) from before initiation of pneumoperitoneum (1.64 mmol/L; 95% CI, 1.33 to 1.94 mmol/L) to 60 minutes after initiation (2.53 mmol/L; 95% CI, 2.22 to 2.83 mmol/L). However, there was not a significant (P = 0.067) effect. Mean arterial lactate concentration had a similar pattern (Figure 7).
Mean arterial lactate concentration for 6 dogs undergoing laparoscopy by use of insufflation with STCO2 (circles) or WHCO2 (squares). Mean arterial lactate concentration increased significantly (P = 0.008) during pneumoperitoneum. There was a significant (P = 0.040) treatment effect and a significant (P = 0.029) time-by-treatment interaction.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
Thromboelastography measurements did not differ significantly between treatments. Reaction time to form a clot did not differ significantly between treatments (P = 0.330) or over time (P = 0.680). There was a significant sex effect for reaction time (P = 0.023) and coagulation index (P = 0.013), with slightly more hypercoagulability for male dogs. There was no significant effect of treatment (P = 0.256) or sex (P = 0.089) for clot strength or MA. However, MA increased significantly (P < 0.001) in the postoperative period, with a median MA of 72.4 mm (range, 69.3 to 75.7 mm) at 48 hours, compared with a median MA of 63.9 mm (range, 61.2 to 66.8 mm) at the end of the laparoscopic procedure.
Similar to results for MA, there was no significant (P = 0.280) effect of treatment on G. There was a significant (P < 0.001) increase in the postoperative period, with a median G of 13.3 dynes/s (range, 11.6 to 15.2 dynes/s) at 48 hours, compared with a median G of 9.9 dynes/s (range, 8.7 to 11.4 dynes/s) at the end of the laparoscopic procedure.
Coagulation index did not differ significantly (P = 0.623) between treatments. However, there was a significant effect of sex (P = 0.013) and time (P = 0.001) on the coagulation index, and a significant (P = 0.024) 3-way interaction was found between treatment, time, and sex (Figure 8).
Mean coagulation index for 6 dogs (4 females [white symbols] and 2 males [black symbols]) undergoing laparoscopy by use of insufflation with STCO2 (circles) or WHCO2 (squares). The coagulation index increased significantly (P = 0.001) during the postoperative period. There was a significant (P = 0.024) 3-way interaction between treatment, time, and sex.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
The concentration of CRP was significantly (P < 0.001) higher in the postoperative period, compared with the baseline concentration. No significant difference was detected for treatments (P = 0.671) or sex (P = 0.207). Because of the limit of detection of the IL-6 assay (1 pg/mL), no results were obtained for the female dogs. There was no significant treatment (P = 0.561) or time (P = 0.571) effect for the male dogs (mean IL-6 concentration, 6,422 pg/mL; 95% CI, 4,603 to 8,241 pg/mL).
Scanning electron microscopy revealed some subjective differences between dogs when insufflation was achieved with STCO2 and with WHCO2. Insufflation with WHCO2 appeared to preserve the microvilli of mesothelial cells and the mesothelial cell layer, whereas insufflation with STCO2 was associated with cell loss and desiccation (Figure 9).
Scanning electron microscopy images of peritoneal biopsy specimens obtained 90 minutes after initiation of pneumoperitoneum from a healthy mature dog undergoing laparoscopy by use of insufflation with WHCO2 (A) or STCO2 (B). Notice that insufflation with WHCO2 appeared to preserve the microvilli and mesothelial cell layer, whereas insufflation with STCO2 resulted in the loss of microvilli and mesothelial cells. Sputter-coated with gold-palladium; bar = 10 μm.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1321
The number of postoperative pain scores > 0 was significantly (P = 0.041) higher, and dogs were 13.9 times as likely to have a score > 0, for the WHCO2 treatment, compared with results when pneumoperitoneum was established with STCO2. However, none of the dogs had a pain score that indicated the need for rescue analgesia. The number of pain scores > 0 decreased significantly (P = 0.012) over time; dogs were more likely to have a score > 0 within 4 hours after the laparoscopic procedure.
Discussion
Results of the study reported here suggested that there was limited benefit for the use of WHCO2 for the induction of pneumoperitoneum in this cohort of 6 healthy mature purpose-bred dogs undergoing laparoscopy. Limited differences were recorded between treatments, and the differences that were detected were of minor clinical importance. Additional studies are needed to evaluate the potential for preservation of the peritoneal mesothelium by the use of WHCO2 before WHCO2 can be recommended for use in clinical cases.
Postoperative hypothermia affects the time needed for recovery from anesthesia in dogs30 and humans.31 In a study30 of the effects of hypothermia on recovery from anesthesia for 69 dogs, there was a prolonged recovery time when the dogs were hypothermic (< 37°C). Mean ± SD amount of time for dogs with a core body temperature of 35° to 35.4°C to successfully attain sternal recumbency was 23.4 ± 22.1 minutes, compared with a mean time of 7.7 ± 3.8 minutes for normothermic (> 38°C) dogs.30 Hypothermic human patients scored to determine fitness for discharge required 40 minutes more to recover from anesthesia when body temperature was 2°C lower, which was nearly twice the duration of recovery for normothermic patients.31
Core body temperature for the dogs of the present study was 0.7°C lower for the WHCO2 treatment than the STCO2 treatment across all time points. This counterintuitive temperature difference suggested a lack of protection against surgical hypothermia for insufflation with WHCO2 in this small cohort of dogs. The reason for the negligible protective effect may potentially have been attributable to interspecies variation in total peritoneal surface area32 or the total volume of insufflated CO2.9 The total peritoneal surface area in adult dogs, compared with that in humans, is unknown, but if the total peritoneal surface area in dogs is substantially less than in humans, it could contribute to less protection because of less warming of this surface. Multiple randomized human clinical trials18,19,21 have revealed no difference in core body temperature between insufflation with WHCO2 and STCO2. In a recent meta-analysis,33 no changes in core body temperature were associated with warmed CO2, compared with STCO2, with or without humidification. Investigators of 1 study16 reported a questionable thermoregulatory benefit for use of WHCO2, with an increase in intraoperative core body temperature of 0.3°C for human patients undergoing laparoscopic cholecystectomy with WHCO2, compared with results for use of STCO2.
In the present study, standard methods for preservation of core body temperature were provided for all dogs. Warming blankets minimize heat loss in the second phase of surgical hypothermia following redistribution15 and can increase core body temperature by 0.9°C, compared with core body temperature in patients who receive no active warming.34 In a study19 conducted to evaluate the thermoregulatory benefits of WHCO2 in human patients undergoing laparoscopic fundoplication, use of a heating blanket did not result in a difference in core body temperature.
The concern about CO2-associated heat loss during laparoscopy was first established in a study9 published in 1991. The authors of the study9 postulated that hypothermia during laparoscopy was associated with liquid evaporation from the peritoneal surface to saturate the CO2 particles and was related to the total volume of CO2 insufflated or to CO2 leaking from port sites.7 Other researchers have found the relative contribution of CO2-associated heat loss is minimal, with 4,800 L of CO2 calculated as the amount required to cause a decrease of 1°C in a 70-kg person.35 The mean total volume of CO2 insufflated in the dogs of the study reported here was 13 L and did not differ significantly between treatments, but it was a volume of CO2 considerably smaller than that typically used for human laparoscopy.36 This minimal volume of CO2 used in the dogs of the present study may help explain the reason that there was no difference in core body temperature with insufflation of WHCO2. Patients in which a higher volume of CO2 is used may receive a stronger protective effect with the use of WHCO2 insufflation. Furthermore, only 1 instrument portal was placed in the dogs of the present study, and a minimal number of instrument passages were performed during peritoneal biopsy. This would not represent the situation for clinical cases in which a much larger number of instrument passages would be performed, which would allow for leakage of CO2 and, subsequently, use of a greater volume of CO2. Regardless, it is unlikely that additional instrument portals or more instrument passages would have considerably increased the total volume of CO2 insufflated.
No clinically relevant difference was noted between treatments for any of the cardiorespiratory variables measured. Abdominal insufflation at high intra-abdominal pressures (> 15 mm Hg) has been associated with reduced venous return and a subsequent reduction in cardiac output.37–39 Insufflation with CO2 in dogs undergoing laparoscopy results in a decrease in SV, but a concurrent increase in HR means the cardiac output is minimally affected.40,41 In the study reported here, HR increased for the duration of the laparoscopic procedure, and SVI increased for 30 minutes after induction of pneumoperitoneum. Consequently, both cardiac output and cardiac index increased and remained elevated throughout the procedure after the induction of pneumoperitoneum for both treatments.
In the study reported here, pneumoperitoneum was induced with CO2 administered to an intra-abdominal pressure of 10 mm Hg, which is similar to a clinical scenario. The paradoxical increase in cardiac output may have been associated with the cardiostimulatory effects of Paco2, surgical stimulation, or displacement of splanchnic volume as a result of the increased abdominal pressure.38,40 Investigators of a study42 of pigs found a similar increase in cardiac output; however, the authors attributed that finding to an increase in HR of individual pigs and did not believe this was representative of the entire study population.
A treatment-by-sex interaction was detected for cardiac output. Males had a nonsignificantly higher median cardiac output for insufflation with STCO2 than for insufflation with WHCO2. Furthermore, the recorded difference in cardiac output was 0.4 L/min, which was of questionable clinical relevance because all values were within reference limits.27 This sex-by-treatment interaction may have been the result of an elevation in HR earlier during the procedure in males than in females. In an exercise study43 of humans, females had a lower cardiac index than did males, which was associated with an inability to adequately increase HR and accommodate for any decrease in SV. It was postulated that this inability is attributable to a blunted sympathetic response and higher vasodilatory state. In contrast, other studies44,45 have found similar values for cardiorespiratory variables in males and females during exercise.
An increase in HR after induction of pneumoperitoneum in dogs of another study40 was attributed to the cardiostimulatory effects of an increase in Paco2. This elevation in HR could also have occurred as a result of the surgical stimulation of portal placement and peritoneal biopsies in the present study. However, peritoneal biopsies were performed only at 0, 30, and 90 minutes, and no spikes in HR were recorded at those times.
In contrast to the increased SVI detected after the induction of pneumoperitoneum in the present study, a decrease in SV was reported for cats undergoing laparoscopic ovariohysterectomy but not for cats undergoing a comparatively shorter laparoscopic procedure (ovariectomy).41 The difference in surgery time between the procedures was estimated to be 50 minutes, and it was suggested that the decrease in SV during longer procedures is attributable to a reduced venous return.41 Similarly, a study40 of dogs also revealed a decrease in SV after the onset of pneumoperitoneum, with a decrease in mean SV from 31.5 to 25.5 mL/beat within the first 15 minutes of the procedure.
An increase in CVP was detected during the first 30 minutes of the procedure in the present study, which indicated an increase in fluid volume and therefore an increase in right atrial pressure. Preload and its effects on SV and cardiac output can be assessed through CVP, which can be used as a surrogate measure and is an indicator of the volemia status of a patient.46 No discernible trends in CVP have been detected in other studies39,40 conducted to evaluate cardiovascular variables in dogs undergoing laparoscopy. Dogs of the study reported here were healthy and normovolemic, and the increase in CVP may have been an artifact associated with transmission of increased intra-abdominal pressure across the diaphragm.42
Afterload, another factor of SV, is primarily determined by SVR, with vasodilation decreasing the amount of wall stress the ventricle needs to overcome during systole to eject the volume. A reduction in SVR and afterload results in an increase in venous return and cardiac output.46 No discernible pattern was evident for SVR; however, a sex-by-treatment interaction was detected, with a higher SVR in male dogs when insufflated with WHCO2 and, conversely, a higher SVR in female dogs when insufflated with STCO2. This is in concurrence with the finding of an elevated cardiac output when male dogs were insufflated with STCO2. The cause for this sex effect is unknown, and it may have been attributable to the fact the WHCO2 had a slower evaporation rate in male dogs with less subsequent hypercapnia and vasodilation. This partially fits with the finding in the present study that male dogs had less notable hypercapnia than female dogs.
The MAP and DAP were 5 mm Hg higher for STCO2 insufflation than for WHCO2 insufflation, with female dogs typically having the most persistent elevations. However, this was a nonsignificant finding and of limited clinical relevance with regard to the magnitude of change. It probably was related to an increase in SVR that resulted from cardiostimulation.40
Abdominal insufflation with CO2 in dogs can lead to hypercapnia and acidosis as a result of absorption in the systemic circulation.47 Overall, Paco2 decreased after the induction of pneumoperitoneum, and it returned to a baseline value of 56 mm Hg after the first 5 minutes. Subsequently, the arterial and venous pH increased initially. This is in contrast to results of other studies40,42,47,48 in which arterial pH decreased in a more linear manner during pneumoperitoneum. In a 2008 study,47 peritoneal fluid pH was evaluated by use of nonsterile litmus paper, whereas investigators of another study49 validated peritoneal pH with pH probes. In that 2008 study,47 local peritoneal acidosis occurred within the first 20 minutes after insufflation, and the pH then appeared to stabilize; however, systemic hypercapnia and acidosis persisted for the duration of the procedure. This led to the conclusion that peritoneal acidosis was a local effect and not related to systemic absorption.47 Peritoneal fluid pH was not measured in the present study because the use of nonsterile litmus paper was considered to be inappropriate.
The increase in venous and arterial lactate concentrations in the present study was attributed to a reduction in perfusion associated with an increase in intra-abdominal pressure and anesthesia. In contrast, investigators of another study48 found no difference in blood lactate concentrations over time or over a range of intra-abdominal pressure of 4 to 15 mm Hg in cats undergoing laparoscopy. The higher mean arterial lactate concentration for females insufflated with STCO2, compared with the concentration for females when insufflated with WHCO2, and for female dogs, compared with male dogs, was likely clinically unimportant because both values were within the reference range.50
The Pao2, and consequently Cao2, decreased over the duration of the procedure. This decrease was not physiologically relevant; minimum Pao2 was 211 mm Hg. A decrease in Pao2 was reported in another study40 and it was thought to be the result of a ventilation-perfusion mismatch. The authors of that study40 suggested the use of muscle paralytics to help avoid intrapulmonary shunting by increasing thoracic compliance.
Values for Do2, Vo2, and the oxygen extraction ratio were all increased after induction of pneumoperitoneum, and o2 was higher for the STCO2 treatment, which was most likely attributable to the increase in cardiac index. The clinical importance of this finding was limited because the difference in o2 was only 0.3 mL/min. Surgical hypothermia has been linked to an increase in o251,52; however, the core body temperature of the dogs of the present study would not be consistent with this theory.
The thromboelastography variables MA, G, and the coagulation index significantly decreased for both treatments during laparoscopy, but the clinical importance of this finding was likely minimal because no values were below reference limits at any time point. Coagulation impairments in hypothermic patients can be seen with core body temperatures < 37°C12–14,31; however, none of the dogs of the present study were considered to be hypocoagulable. Conversely MA, G, and the coagulation index increased to above established reference limits, which suggested hypercoagulability associated with a systemic inflammatory response during the postoperative period for both treatments. A general pattern of hypercoagulability was also evident in the male dogs, with the biggest difference seen at 24 hours after laparoscopy. This is in contrast to another study53 of dogs in which investigators found no effect of sex on thromboelastography results. An inverse effect of sex has been reported54 for humans wherein females, especially pregnant females, have higher coagulability than males because of higher concentrations of fibrinogen and factor VIII and lower concentrations of protein S.
No treatment effect was detected for CRP concentration, but concentrations increased after laparoscopy, with the highest concentration recorded 12 hours after the procedure. This is in concurrence with the CRP concentrations for dogs undergoing laparoscopic ovariohysterectomy in another study.25 The CRP concentrations in the present study were consistent with mild surgical inflammation (mean concentration at 12 hours, 32 mg/mL) because the reference range is 9 to 30 mg/mL for clinically normal dogs.55 However, the CRP concentration is > 300 mg/mL for dogs with pyometra.55
The limit of the detection of the IL-6 assay was 1 pg/mL. Unfortunately, none of the female dogs had a detectable IL-6 concentration. A range for IL-6 of 1 to 400 pg/mL was reported in clinically normal animals of another study.55 The mean IL-6 concentration for the male dogs of the present study was 6,422 pg/mL, which was consistent with moderate surgical inflammation. The sex-by-treatment interaction for the dogs of the present study is in contrast to that reported56 for human patients, wherein females often have higher concentrations of inflammatory cytokines. Findings for the study reported here were consistent with higher sympathetic tone and subsequent suppression of proinflammatory cytokines; however, they may have been a result of type II error.
In concurrence with results of other studies,23,49,57 a subjective assessment of peritoneal biopsy specimens revealed evidence of mesothelial cell loss, which can be associated with local peritoneal acidosis and mesothelial hypoxia after insufflation with STCO2. The benefit of less peritoneal irritation in canine patients is unknown, and it is postulated that less peritoneal injury results in a lower likelihood of adhesion formation, which is an important complication in human patients undergoing laparoscopic surgery.24 Peritoneal adhesions can lead to intestinal obstruction, chronic pelvic pain, infertility in females, and difficulties during subsequent abdominal surgeries.58 Although abdominal adhesions have not been reported for clinical veterinary patients that have undergone laparoscopy, they have been reported for research dogs undergoing laparoscopy.59 The denuded peritoneum seen for insufflation with STCO2 would also be more susceptible to the implantation of cancer cells.60 In addition, WHCO2 can induce apoptosis and inhibit proliferation, migration, invasion, and adhesion of human colon cancer cells.61 Portal site metastasis is a common concern in human medicine,61,62 but there is only 1 report63 in the veterinary literature. The importance of the peritoneal preservation evident when dogs were insufflated with WHCO2 is unknown, but potential advantages with regard to a reduction in adhesions and tumor implantation may be seen. Further studies are needed to evaluate this potential benefit.
We used the short-form Glasgow Composite Pain Scale to assess signs of postoperative pain; that scale has been established as a repeatable and reliable method of pain assessment in veterinary medicine.64 In a study65 in which investigators used the short-form Glasgow Composite Pain Scale to assess dogs undergoing laparoscopic ovariohysterectomy by use of STCO2 or lift laparoscopy, there was no difference at any time point after surgery, with only a moderate correlation (r = −0.492) with results of esthesiometry. There are conflicting results in the human literature with regard to the potential analgesic effects of WHCO2. Investigators of several studies16,17,21,66 documented a reduction of pain in surgical patients with the use of WHCO2, compared with pain after use of STCO2; however, there are several other studies18,19,34,67 in which investigators detected no difference in pain scores. In a randomized clinical trial of 53 women undergoing laparoscopic gynecologic surgery, use of WHCO2 resulted in a slightly higher postoperative pain score and was associated with less patient satisfaction.68
A potential limitation of the study reported here was that the mild hypothermia may not have been sufficient to cause significant differences in the study outcomes. However, it has been suggested11,15 that any degree of hypothermia < 37°C can be sufficient to cause impaired hemostasis; thus, we believe that this mild hypothermia was appropriate for the study design. Additionally, the mild hypothermia in the present study is similar to that observed in most veterinary hospitals and should have been more clinically relevant than moderate or marked hypothermia. Another potential limitation was the lack of differentiation between the CO2 treatments. The WHCO2 (37°C and 98% relative humidity) was compared directly with STCO2 (22°C and 0% relative humidity); we did not include treatments of warmed CO2 (37°C and 0% relative humidity) or humidified CO2 (22°C and 98% relative humidity). The omission of these treatments was based on results of studies69,70 of humans in which it was found that warmed CO2 and humidified CO2 as separate insufflation treatments were of limited benefit in preventing hypothermia and may even have resulted in greater postoperative pain. Finally, only 2 male dogs were included in the study; therefore, the relevance of any sex effect is questionable. Although interactions with sex were included to provide complete results, it is the authors’ opinion that any sex effect was likely attributable to type 1 error.
Analysis of data for the study reported here suggested there was no cardiorespiratory or thermoregulatory benefit for the use of WHCO2 to create pneumoperitoneum in healthy mature dogs undergoing laparoscopy. Some advantages may exist for local peritoneal desiccation and associated complications related to tumor cell implantation and metastasis at portal sites.60–63 Further study is required before use of WHCO2 can be recommended for clinical cases.
Acknowledgments
Supported by the OVC Pet Trust and Lexicon Medical.
The authors have no conflicts of interest to declare.
The authors thank William Sears and Gabrielle Monteith for assistance with the statistical analysis.
ABBREVIATIONS
| Cao2 | Arterial oxygen concentration |
| Ccvo2 | Central venous oxygen concentration |
| CI | Confidence interval |
| CRP | C-reactive protein |
| CVP | Central venous pressure |
| DAP | Diastolic arterial blood pressure |
| Do2 | Oxygen delivery |
| ETISO | End-tidal concentration of isoflurane |
| G | Clot elasticity |
| HR | Heart rate |
| IL | Interleukin |
| LiDCO | Lithium dilution cardiac output |
| MA | Maximum amplitude of blood clot |
| MAP | Mean arterial blood pressure |
| Petco2 | End-tidal partial pressure of CO2 |
| SAP | Systolic arterial blood pressure |
| STCO2 | Standard-temperature CO2 |
| SV | Stroke volume |
| SVI | Stroke volume index |
| SVR | Systemic vascular resistance |
| o2 | Oxygen consumption |
| WHCO2 | Warmed humidified CO2 |
Footnotes
Ott DE. Reduction of the inflammatory response using wet CO2 during laparoscopy (abstr). J Am Assoc Gynecol Laparosc 2002;9:542.
Microsoft Excel, version 14.7, Microsoft Corp, Redmond, Wash.
BD, Franklin Lakes, NJ.
Sandoz, Boucherville, QC, Canada.
Fresenius Kabi, Toronto, ON, Canada.
Zoetis Inc, Parsippany, NJ.
S/5 anesthesia monitor, GE Healthcare, Madison, Wis.
DOT-34 NRC 300/375 M1014, Datex-Ohmeda Division, Helsinki, Finland.
S/5 Aespire 7900 ventilator, GE Healthcare, Madison, Wis.
Bair-hugger, 3M, Saint Paul, Minn.
Acklands Grainger, ON, Canada.
Baxter Corp, Mississauga, ON, Canada.
Mila International Inc, Florence, Ky.
LiDCO Ltd, London, England.
Flow-through cell electrode assembly, LiDCO Ltd, London, England.
ABL90 flex blood gas analyzer, Radiometer, Brea, Calif.
0.15 mmol/mL, LiDCO Ltd, London, England.
6-mm laparoscopic cannula, Karl Storz Endoscopy, Goleta, Calif.
Insuflo, provided by Lexicon Medical, Saint Paul, Minn.
Endoflator, Karl Storz Endoscopy, Goleta, Calif.
Laparoscope, Karl Storz Endoscopy, Goleta, Calif.
TEG 5000 thrombelastograph hemostasis analyzer system, Haemonetics, Braintree, Mass.
Kaolin, Haemonetics, Braintree, Mass.
5-mm round cup biopsy forceps, Karl Storz Endoscopy, Goleta, Calif.
Emitech K550 sputter-coater, Ashford, Kent, England.
Hitachi S-570 scanning electron microscope, Hitachi High Technologies Inc, Tokyo, Japan.
Pfizer, New York, NY.
Metacam, Boehringer Ingelheim, Burlington, ON, Canada.
PROC GLM, SAS, version 9, SAS Institute Inc, Cary, NC.
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