Gunter, Joel B. MD*; Ball, John AS, BMET†; Than-Win, Sean BMET†
It is recommended that patients susceptible to malignant hyperthermia (MH) be anesthetized using anesthesia machines free of residual halogenated anesthetics.* This can be achieved either by using a dedicated “clean” anesthesia machine or by flushing residual halogenated anesthetics from the anesthesia machine before use. It has recently been demonstrated that many newer anesthesia machines require much longer flush procedures than older, conventional anesthesia machines to achieve acceptable residual halogenated anesthetic concentrations.1–4
Prompted by these observations, we studied clearance of sevoflurane from the Dräger Fabius anesthesia machine (Dräger Medical, Telford, PA) and attempted to identify methods of accelerating the flushing process.
Before each experiment, the anesthesia machine to be tested (Narkomed GS or Fabius, Dräger Medical, Telford, PA) was equilibrated with 3% sevoflurane in oxygen 3 L/min for 2 h (pediatric circuit, 2 L breathing bag, 2 L bag as artificial lung [Vital Signs, Totowa, NJ], tidal volume (VT) = 600 mL, rate = 10/min, inspiratory to expiratory ratio (I:E) = 1:2, no inspiratory pause). Once equilibrated with 3% sevoflurane, the machine was prepared according to our protocol for the MH susceptible patient: the vaporizers were removed, the CO2 absorbent (Amsorb® Plus, Keomed, Minnetonka, MN) was changed, and a clean breathing circuit, breathing bag, and artificial lung were installed.
Residual sevoflurane concentrations were measured with the Miran SapphIRe XL ambient air analyzer (Thermo Fisher Scientific, Waltham, MA), a portable infrared spectrophotometer capable of measuring sevoflurane to <1 ppm. Samples are drawn through a sample wand, typically held by the operator and directed toward the area to be sampled, into the 2.23 L sample chamber by a continuous pump at a nominal rate of 14 L/min. In order to minimize continuous and retrograde flow in the inspiratory limb of the breathing circuit, the Miran SapphIRe XL was connected to the breathing circuit as shown in Figure 1, creating a loop in the inspiratory limb. The gas analyzer was zeroed in the test area before each experiment according to the manufacturer's recommendation.
After preparation of the anesthesia machine and gas analyzer, the flush procedure was initiated. The oxygen flow was set to 10 L/min and the ventilator cycled as outlined above (VT = 600 mL, rate = 10/min, I:E = 1:2). Readings from the gas analyzer were initially made at 1 min intervals. As time passed and the rate of change slowed, the interval between readings was allowed to lengthen. Depending on the experiment, readings continued until the residual sevoflurane concentration was <10 ppm, <5 ppm, or had demonstrated a pattern indistinguishable from a previous run or experiment.
Equilibration of the Miran Ambient Air Analyzer
Based on its pump flow of 14 L/min and sample chamber volume of 2.23 L, 95% equilibration of the Miran sample chamber would be expected to take about 25–30 S (half-time [t1/2] = 0.693/14/2.23 = 6.6 S; 4 half-times to 95% equilibration; Appendix). However, the operation of the anesthesia machine and the experimental setup served to prolong equilibration of the sample chamber to a step change in concentration. In the Dräger Fabius anesthesia machine, gas delivery into the inspiratory limb occurs primarily during inspiration; given an I:E ratio of 1:2, the actual 95% equilibration time would therefore be expected to be about 3 times longer than that calculated above, or about 90 S. Finally, the loop configuration of the sample and return lines for the gas analyzer resulted in partial immediate resampling of gases returned from the analyzer (Fig. 1). As the Miran sample flow rate (14 L/min = 233 mL/S) and ventilator inspiratory flow rate (VT = 600 mL, inspiratory time [TI] = 2 S, inspiratory flow rate = 300 mL/S) are approximately equal, the actual 95% equilibration time can be expected to double again, to at least 3 min. The slow equilibration of the sample chamber with the breathing circuit has minimal impact on the analysis of processes whose half-times are much longer than 3–5 min (data collected before 5 min were excluded from the regression analysis), but does make it impossible to describe faster processes using this experimental apparatus.
Initial Clearance of Sevoflurane
The initial clearance of the breathing system from sevoflurane concentrations of 3% to trace concentrations of sevoflurane (<0.1%, 1000 ppm) was therefore examined using a modification of the procedure above. The preparation period was shortened to 10 min using the settings outlined above. Sevoflurane concentrations were sampled at the Y-piece of the circuit and measured using a SAM® infrared gas analyzer in conjunction with a Solar 8000M monitor (GE Healthcare, Milwaukee, WI); samples were returned to the circuit after analysis. Residual sevoflurane concentrations were recorded every 5 s until they were ≤0.1% (1000 ppm, approximately 120 s).
For purposes of analysis, the breathing system was modeled as a single compartment flushed by a continuous flow of fresh gas (Appendix). An estimator for the equilibration time constant was obtained from the slope of the log-linear regression of concentration (dependent variable) upon time (independent variable); confidence in the model was based upon examination of the coefficient of determination (r2) of the regression. All analyses were performed using SPSS for Windows v 15.0 (SPSS, Chicago, IL).
The results of two runs examining the initial clearance of sevoflurane from the breathing system using the modified procedure described above are shown in Figure 2. After a step change from 3% to 0% delivered sevoflurane, there was a lag of 10 s before any change was seen in the sampled concentration; this probably represented a combination of the dwell time (transit time) of the sample line and the time required for fresh Vt to reach the inspiratory limb of the circuit. The half-time of initial clearance was 19.8 S (r2 = 0.946). Clearance to 0.15% (95%) and 0.03% (99%) would be expected to take 80 and 132 s, respectively. The initial clearance of sevoflurane is therefore complete by the time the Miran ambient air analyzer has equilibrated with the breathing circuit.
Analysis of the Dräger Fabius anesthesia machine proceeded in several stages, as various maneuvers to accelerate clearance of sevoflurane were explored. Descriptions of the experiments follow, and results are summarized in the Table 1.
As a control, the experimental apparatus was first tested on a conventional anesthesia machine (Dräger Narkomed GS). Before the experiment, the Narkomed GS was prepared in the same manner as described above. The time required to achieve a residual sevoflurane concentration <5–10 ppm was of the order of 15–20 min (Fig. 3A).
Experiments 1A and 1B
Base Experiment—Experiment 1A was performed using the preparation routine and testing apparatus described above; achievement of a residual concentration of sevoflurane <5–10 ppm took much longer than in the conventional anesthesia machine (Fig. 3B). Open System—Based on the consideration that the results of Experiment 1A might have been related to failure to adequately circulate the gas in the breathing bag, the tail of the bag used as an artificial lung was cut off, resulting in a large leak (Experiment 1B). As the breathing bag serves a reservoir of gas to refill the ventilator piston during exhalation, a large leak might have been expected to result in greater turnover of the gas in the breathing bag. However, the results of Experiments 1A and 1B were indistinguishable (Fig. 3B and Table 1).
Experiments 2A, 2B, and 2C
These experiments involved increasing the flow of fresh gas into the breathing circuit during the flush procedure. Increased Circuit Flow—In Experiment 2A, an additional 10 L/min of oxygen was delivered via the auxiliary oxygen flowmeter into the circuit Y-piece. No appreciable acceleration of clearance of residual sevoflurane was noted (Table). Increased Flow to Ventilator—In an attempt to improve flushing of the ventilator piston, an additional 10 L/min of oxygen was delivered either into the ventilator drive hose (Experiment 2B; Fig. 4) or retrograde to the ventilator piston via a co-axial hose inside the ventilator drive hose (Experiment 2C; Fig. 4 inset). While both Experiments 2B and 2C seemed to modestly accelerate clearance of residual sevoflurane (Fig. 3C and Table), this advantage was lost when the additional oxygen flow was discontinued, suggesting that the effect was simply due to dilution (Fig. 3C; note starred data points).
Interposed Bellows Ventilator—In order to exclude the ventilator piston as the reservoir of residual sevoflurane, a clean bellows ventilator assembly was placed between the piston ventilator and the breathing system. The piston ventilator was then used to drive the bellows ventilator (Fig. 5). With the system configured in this fashion, there was a modest improvement in clearance of residual sevoflurane (Fig. 3D and Table); however, the improvement was not sufficient to merit adoption of this approach or further validation of the system's ability to accurately and safely ventilate patients' lungs.
Charcoal Scrub—Abandoning attempts to accelerate the clearance of residual sevoflurane, the final experiment explored the possibility of “scrubbing” trace anesthetics from the inspiratory limb of the circuit. The QED® (Quick Emergence Device, Anecare Laboratories, Salt Lake City, UT) is a commercially available circuit adjunct containing activated charcoal and an expandable length of corrugated tubing. In its intended application, it is inserted between the circuit Y-piece and the endotracheal tube. The expandable tubing acts as an adjustable source of dead-space (leading to rebreathing of exhaled CO2), while the activated charcoal removes inhaled anesthetics from the exhaled gas. In Experiment 4, the QED device was mounted on the inspiratory port of the breathing system (Fig. 6), and preparation of the anesthesia machine and circuit were otherwise according to the protocol above. In order to avoid unnecessary saturation of the activated charcoal, the device was only activated after an initial 5 min flush of the circuit and ventilator. Within 5 min of activating the QED, the sevoflurane concentration in the inspiratory limb was <10 ppm; the change was probably instantaneous, with the delay representing the time required to equilibrate the analyzer (Fig. 7A and Table). To confirm an adequate capacity for the device, after maintaining fresh gas flows at 10 L/min for the first 15 min, the oxygen flow rate was decreased to 2 L/min and measurement of residual sevoflurane continued for 6 h (Fig. 7B). To assess the concentration of sevoflurane remaining in the breathing system during use of the QED, the device was intermittently turned off and the breathing system and analyzer were allowed to equilibrate before reactivating the device.
The coefficient (inverse time constant) from the log-linear regression provides only an estimate of the ratio of the effective fresh gas flow rate (QFG) and breathing system volume (Vds); calculation of the total mass of residual sevoflurane contained in the Fabius breathing circuit and ventilator requires a determination of the actual value of Vds (total mass = initial concentration (C0) · Vds, analogous to total dose = initial concentration X volume of distribution). Although the oxygen flow rate and minute volume are known, the actual effective fresh gas flow into the circuit is not simply the delivered oxygen flow and cannot be determined from first principles. We attempted to estimate the mass of sevoflurane retained in the breathing system as follows.
Estimate of Actual Circuit Volume
Making the assumptions that QFG was the same during the bulk (early) clearance and trace (late) clearance phases and that Vds during the early phase was equal to actual breathing system volume (VCIR), it is possible to estimate QFG, and thus Vds during the late phase, provided that an estimate of actual VCIR could be obtained. After equilibrating the breathing circuit and test lung with 5% sevoflurane in 100% oxygen for 10 min, 100 mL of gas from the circuit was drawn into two 50 mL-syringes attached to the circuit Y-piece via a four-way stop-cock. Sevoflurane delivery was then discontinued and the system flushed with 100% oxygen until the residual sevoflurane concentration (SAM module) was 0% for 5 min. Oxygen delivery was then discontinued and the breathing system and ventilator continued to run in “closed circuit” mode. After 5 min in closed circuit mode with a measured sevoflurane concentration of 0%, the reserved 100 mL of 5% sevoflurane (5 mL of sevoflurane vapor) was returned to the system. Using the subsequent concentration of sevoflurane measured in the breathing system (0.2%–0.3%), it was possible to calculate the effective circuit volume into which the returned sevoflurane was diluted (VCIR = 1700–2500 mL).† As the nominal volume of the breathing system reported by the manufacturer is 2800 mL, exclusive of the breathing bag and not accounting for the volume displaced by the CO2 absorbent,5 an estimate of 2000 mL for VCIR seems reasonable.
Estimate of Effective Fresh Gas Flow
Based on the value of QFG/Vds from the early phase clearance experiment (0.035 s−1), QFG can then be estimated to be 2000 mL·0.035 s−1 = 70 mL/s (4200 mL/min).
Estimate of Effective Breathing System Volume
Using the estimate of QFG/Vds from the late phase measurements (0.024 min−1), Vds is estimated to be 160 L (4200 mL · min−1/0.024 min−1), which is obviously much greater than the actual system volume. This can be considered to be analogous to the case of highly lipid-soluble drugs, where the calculated volume of distribution may be much greater than the actual patient volume.
Estimate of Retained Mass of Sevoflurane
Given an initial late phase sevoflurane concentration of 60 ppm and Vds = 160 L, the actual total mass of sevoflurane retained by the Fabius breathing system and ventilator is estimated to be approximately 10 mL of vapor (approximately 100 mg).‡
Clearance of residual trace concentrations of sevoflurane required approximately 6 times as long for the Dräger Fabius anesthesia machine as for the Dräger Narkomed GS anesthesia machine. This difference was due to a combination of a higher initial C0 (61 vs 29 ppm) and a much longer t½ (29 vs 7 min) for the Fabius machine. The time required for the Fabius machine to achieve a residual sevoflurane concentration <5 ppm (105 min) was even longer than that previously reported for the Dräger Primus (Apollo) anesthesia machine (65 min)3; however, this difference may have been due to the higher concentration of sevoflurane used in the preparation procedure in our study (3% vs 2.5%).
There are several possible reasons for the slow clearance of trace sevoflurane from the Dräger Fabius anesthesia machine compared to older, conventional anesthesia machines. The first of these relates to the design of the Fabius breathing system and the operation of the piston ventilator. The unique operational features of the Fabius breathing system are similar to those of the Dräger Primus (Apollo) platform, which have been well described previously.3,4 To briefly recap (Fig. 8), during inspiration, fresh gas is diverted via the fresh gas decoupling valve through the CO2 absorber to either the breathing bag or the scavenging system; the delivered Vt therefore consists of gas from the inspiratory limb of the breathing circuit and the ventilator. During exhalation, the ventilator piston refills with a combination of exhaled gas from the patient, fresh gas, and gas from the breathing bag. When configured with minimal leak, as in our basic experimental setup, the system is extremely efficient in recirculating exhaled gases. With the exception of that drawn into the piston during its return stroke, most fresh gas delivered into the system is simply lost out of the scavenging system, either via fresh gas decoupling or during the expiratory phase after the piston has refilled. We considered the possibility that the observed delayed clearance of trace sevoflurane might have been due to this very efficiency and, therefore, intentionally decreased system efficiency in Experiment 1B. However, despite introducing a large leak and the resultant increased entrainment of fresh gas, clearance of trace sevoflurane was not accelerated.
A second unique feature of the Dräger Fabius anesthesia machine is the piston ventilator itself. With the exception of the positive and negative pressure relief valves, which open only under extraordinary circumstances, the piston itself is a dead end; the ventilator spill valve is located in the breathing system, where it is configured as an open bypass of the adjustable pressure limiting valve (Fig. 8). This is in contrast to older, bellows-type ventilators, where excess gas return to the bellows is vented via a spill valve located within the ventilator. We therefore considered the possibility that our observations were due to stagnant gas in the ventilator piston which was not being turned over. To increase ventilator washout, additional fresh gas was delivered directly into the ventilator drive hose or the ventilator itself in Experiments 2B and 2C. Although there was a modest acceleration of trace sevoflurane clearance under these conditions, discontinuation of the additional fresh gas flow resulted in a return of the residual concentrations to the level expected in the absence of the additional fresh gas flow. The most likely explanation for this observation is that the additional fresh gas served simply to “dilute” the concentration of sevoflurane; the actual residual concentration within the components of the breathing system was unchanged and the measured concentration reverted to its true value when the diluting gas was eliminated.
The third possible explanation for delayed clearance of sevoflurane from the Dräger Fabius anesthesia machine is that it is more soluble in the synthetic components of the Fabius breathing system.6–8 This is certainly compatible with our observations, in that the C0 for the Narkomed GS was less than that for the Fabius (29 vs 61 ppm). The longer clearance half-time seen in the Fabius implies that diffusion of sevoflurane out of its synthetic components is slower than that from the components of the Narkomed GS anesthesia machine, and is probably the rate-limiting step in the clearance process. It seems that components in both the ventilator and the breathing system are implicated, although the effect of the ventilator may be greater. Exclusion of the piston ventilator from the breathing system in Experiment 3 did decrease C0, compatible with a greater residual mass of sevoflurane in the ventilator; however, the actual rate constant observed in Experiment 3 was only about 25% greater than that in Experiment 1, suggesting that diffusion out of the components of the breathing system was only marginally faster than out of the components of the ventilator.
If we assume that diffusion into the synthetic components of the breathing system proceeds at the same rate as diffusion out, the observation that the C0 of sevoflurane was 60 ppm, rather than 3%, suggests that the synthetic components of the breathing system had become saturated with sevoflurane during the 2 h preparation period. Examination of Prinzhausen et al. results reveals concentrations in the 50–100 ppm range at 5 min, compatible with saturation of the components of the Dräger Primus (Apollo) anesthesia machine at a similar concentration of sevoflurane.3 Based on the effective Vds of 160 L estimated above (Results section) and the small actual volume of the synthetic components of the breathing system, the synthetic/gas partition coefficient of sevoflurane must be extremely high for the components of the Fabius breathing system.
Limitations of our data include failure to perform multiple replications of each experiment, failure to perform observations in all experiments to the achievement and maintenance of a residual concentration <5 ppm, and examination of only one halogenated anesthetic (sevoflurane). Although the limited number of runs for each experiment (one, two, or three) certainly makes it impossible to provide a meaningful confidence interval for our observations, the extreme reproducibility of the observations and regression coefficients of determination approaching unity suggest that our results can be viewed with confidence. Sevoflurane is the primary halogenated anesthetic used in our practice and was therefore chosen for our experimental protocol; similar results for isoflurane and sevoflurane were seen in the report from Prinzhausen et al.3, suggesting that the effect is independent of the anesthetic chosen. In addition to the above, the use of two different analytic techniques makes it difficult to produce an integrated model of both early and late phase clearance; future studies would benefit from identification of a single analytical method able to accurately measure instantaneous concentrations during both phases.
The minimum concentration of halogenated anesthetic posing a risk to the MH-susceptible patient is not known. The concentration targets set for our experiments (<10 ppm and <5 ppm) were based on previous descriptions of procedures for flushing anesthesia machines for the MH patient.1–4,9–11 It has been shown that MH-susceptible swine do not trigger in the presence of 10 ppm halogenated anesthetic. §To our knowledge, there are no reports of spontaneous triggering of MH in susceptible humans in the presence of trace halogenated anesthetic concentrations within the National Institute of Occupational Safety and Health limits (2 ppm).∥ Any attempt to pursue definitive human studies to address this question will suffer from obvious ethical limitations.
In the face of these observations and uncertainty regarding the maximum safe exposure limit for halogenated anesthetics for the MH-susceptible patient, several approaches can be considered when anesthetizing an MH-susceptible patient with the Dräger Fabius anesthesia machine. In the absence of evidence supporting the safety of exposure to residual sevoflurane concentrations >10 ppm, we do not believe that a brief flush to remove bulk concentrations of sevoflurane is a tenable solution. However, the time required to perform an adequate flush is likely to prove disruptive to a busy operating room schedule. Use of dedicated “clean” anesthesia machines for MH-susceptible patients entails significant monetary and manpower costs. Crawford et al. have advocated replacing the components of the Apollo breathing system contaminated with halogenated anesthetics with “clean” components before anesthetizing MH-susceptible patients.4 In contrast to the Apollo, where the breathing system can be replaced en bloc, it is our impression that replacement of the Fabius breathing system is a task best left to trained biomedical engineering support personnel.
The ability of activated charcoal to remove in excess of 90% of incident halogenated anesthetics from the inspired gases offers a fifth alternative. Interposition of an activated charcoal filter between the breathing system and the patient can reduce inspired sevoflurane (and presumably other halogenated anesthetic concentrations) to an acceptable level within 5 min. Although there is a monetary cost associated with the use of activated charcoal filters, that cost is more than offset by recovery of potential surgical time (opportunity cost) which would otherwise be lost during switching or flushing anesthesia machines. Our acquisition cost for the QED device ($39) represents about 2 min of operating room time as billed to the patient. Based on our results, a single QED device contains sufficient activated charcoal for at least a 6 h anesthetic. We are unable to estimate the maximum capacity of the QED device; however, after 6 h at a fresh gas flow of 2 L/min, residual sevoflurane concentrations in the Dräger Fabius anesthesia machine were <10 ppm. Therefore, even if the activated charcoal in the QED became completely saturated with halogenated anesthetic at some point after 6 h, the background concentration of halogenated anesthetic in the breathing system should be within the putative safe range.
We have therefore adopted a process referred to as the Five-Five-Five Flush. The Dräger Fabius anesthesia machine is first prepped by removing the vaporizers and replacing the CO2 absorbent. A clean circuit, including a QED on the inspiratory port and a 2 L artificial lung, is then installed and the system is flushed for 5 min with the QED in the “Off” position (Oxygen 10 L/min, Vt = 600 mL, rate = 10/min, I:E 1:2). The QED is then turned “On” and the flush is continued for a second 5 min. The machine is then ready to deliver anesthesia to the MH-susceptible patient, provided that the fresh gas flow is maintained at ≥ 10 L/min for the first 5 min of the anesthetic. After that, fresh gas flow can be adjusted as clinically indicated, maintaining a minimum of 2 L/min of fresh gas throughout the anesthetic. The QED remains on the inspiratory port in the “On” position until the conclusion of the anesthetic and is then discarded.
In conclusion, we have demonstrated that achieving residual sevoflurane concentrations in the <5–10 ppm range in the Dräger Fabius anesthesia machine using conventional flush procedures can require almost 2 h. We were unable to identify any method of significantly accelerating this process, suggesting that the slow clearance of sevoflurane from this machine is due to the materials used in its construction, rather than to its unique breathing system and ventilator design. Additional research will be required to identify the specific components and materials which are responsible for the slow clearance of halogenated anesthetics from the Dräger Fabius and Primus (Apollo) anesthesia machines. A breathing system adjunct containing activated charcoal reduced residual sevoflurane concentrations to <5 ppm within 10 min and maintained those concentrations for at least 6 h. Breathing system adjuncts containing activated charcoal offer a means of rapidly transforming an anesthesia machine contaminated with halogenated anesthetics into a “clean” machine for use in the MH-susceptible patient, and are an attractive alternative to the delay and inconvenience associated with conventional flushing procedures or the use of dedicated “clean” anesthesia machines.
The authors wish to thank Josh Harney of the Children's Hospital Medical Center department of Occupational Safety and Environmental Health for the loan of the Miran SapphIRe XL ambient air analyzer, and instruction in its use and calibration.
For purposes of analysis, the breathing circuit/ ventilator was treated as a single compartment (volume = Vds) containing halogenated anesthetic (initial concentration = C0) flushed with a continuous flow of fresh gas (flow rate = QFG; concentration = CFG); at equilibrium, the concentration in the compartment is equal to that in the fresh gas (CFG). The concentration of halogenated anesthetic in the compartment as a function of time is described by the following differential equation:
A general solution to Eq. 1 is:
For initial conditions C0 > 0 and CFG = 0 (washout), Eq. 2 reduces to:
For initial conditions C0 = 0 and CFG > 0 (wash-in), Eq. 2 reduces to:
Equation (Uncited)Image Tools
These equations are analogous to first-order, single compartment pharmacokinetic models, with QFG and Vds being analogous to clearance and volume of distribution, respectively. The ratio QFG/Vds can be considered as the rate constant, or the inverse of the time constant, for equilibration of the system. The half-time (t½) of wash-in or washout can be calculated analogously to that of half-life for first-order kinetics:
Equation (Uncited)Image Tools
Equilibration to 95% of CFG requires slightly more than four half-times, or three time constants. Cited Here...
Equation (Uncited)Image Tools
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*http://medical.mhaus.org/index.cfm/fuseaction/Content.Display/PagePK/MedicalFAQs.cfm; last accessed March 21, 2008. Cited Here...
†The concentration of sevoflurane (CSEVO) in the breathing system after the addition of 5 mL of sevoflurane vapor (VSEVO) is:
Rearranging and substituting the experimental data, Cited Here...
Equation (Uncited)Image Tools
‡The mass of sevoflurane is the concentration multiplied by the effective volume (160 L · 60 × 10−6 = 9.6 × 10−3 L = 9.6 mL). Based on the molar gas volume at standard temperature and pressure (22.4 L/mole), 9.6 × 10−3 liters of sevoflurane vapor represents 4.3 × 10−4 moles, or 0.086 gm (molecular weight of sevoflurane 200 gm/mole). Cited Here...
Equation (Uncited)Image Tools
§Maccani RM, Wedel DJ, Kor TM, Joyner MJ, Johnson MF, Hall BA. The effect of trace halothane exposure on triggering malignant hyperthermia in susceptible swine. Anesth Analg 1996;82:S287. Cited Here...
∥http://www.osha.gov/pls/oshaweb/owadisp.show_document?_p_table=FACT_SHEETS&p_id=128; last accessed March 21, 2008. Cited Here...