Identification of the Epidural Space

#### **Chapter 1**

## Perspective Chapter: Epidural Administration – Various Advances in Techniques

*Sotonye Fyneface-Ogan and Fiekabo Ogan-Hart*

#### **Abstract**

First described by Fidel Pages in 1921, epidural administration is a technique in which a medicine is injected into the epidural space has undergone various modifications and approaches in recent years. Epidural administration also involves the placement of a catheter into the epidural space, which may remain in place for the duration of the treatment. These advances have changed the face of clinical practice and improved the patient management. Modification to the approach of epidural administration has moved from the single-shot epidural administration to programmed injections. The use of these improved techniques has reduced complications associated with epidural administration and improved care. The administration of medication into this space has been considered as safe and effective for providing pain relief during childbirth and surgery. A review of these modes of administration will highlight the importance of each of the techniques.

**Keywords:** epidural administration, techniques, epidural analgesia, epidural catheter, epidural space

#### **1. Introduction**

Epidural administration of medications has been used in many surgical and anesthetic managements of patients. It is currently mostly used for postoperative management in the regions of the body amenable to it [1]. It has a wide margin of safety in experienced hands. Beyond its use in postoperative pain management, it has been indicated in the administration of steroids, contrast agents and many others.

It is important to know that the positioning of the patients requiring epidural administration is determined by patient's comfort, compliance and preference of the attending. Insertion of the needle is commonly performed in either sitting, or flexed lateral position, although the sitting position has higher rate of first pass insertion and shorter duration (skin puncture to correct needle placement time) [2].

This chapter will review the various methods epidural administration of agents into the epidural space can be achieved.

#### **2. Methods of identifying epidural space**

Epidural administration of pharmacologically active agents would be impossible without proper identification of the space. This is most frequent cause of failed epidural administration [3]. Patient positioning, the use of a midline or paramedian approach, and the method used for catheter fixation can all influence the success rate.

For epidural injection using the midline approach to be successful, the Tuohy needle would have to traverse the skin, subcutaneous fat, supraspinous ligament, interspinous ligament, ligamentum flavum, and then into the epidural space. The epidural space is a potential space, the loss of resistance on a plunger is indicative of the entrance to the epidural space. Localization of the space is one of the major key steps in epidural administration. Many ingenious devices have been designed to improve the success of the puncture procedure and are based on the principle of loss of resistance within the epidural space.

#### **3. Epidural space identification methods**

1.Ogan's slingshot epidural syringe: This simple device uses a rubber sling mounted on the plunger of the syringe which generates a head pressure on the plunger (**Figure 1**) [4].

With a mounted Tuohy needle advancing into the epidural space, the plunger collapses as the needle gets into the epidural space. This device which depends on loss of resistance to air gives about 95-97% accuracy in identifying the epidural space.

2.Epidural balloon: This is also a device which depends on the negative pressure exhibited by the denting of the ligamentum flavum during penetration of the Tuohy needle (**Figure 2**).

The balloon attached to plastic device collapses (or the air in the balloon is sucked in) as the needle enters into the epidural space.

3.Episure™ AutoDetect syringe: This is another epidural space localization device (**Figure 3**).

**Figure 1.** *Slingshot® epidural syringe.*

*Perspective Chapter: Epidural Administration – Various Advances in Techniques DOI: http://dx.doi.org/10.5772/intechopen.108642*

**Figure 2.** *Epidural balloon – Vygon© UK.*

This device works better when it is filled with normal saline and with an advancing mounted Tuohy needle into the space the plunger automatically loses resistance, which "provides an objective, visual confirmation that the epidural space has been identified." Other devices used in the identifying the epidural space include the use of ultrasound guide [5], spring-loaded syringes, episure [6].

4.Epidrum©: This device depends on a low pressure loss of resistance to facilitate epidural space identification. The device is fixed between the syringe and needle and, filled with air to inflate its diaphragm. As the needle advances and gets into the epidural space, there will be a visible collapse of the diaphragm marking the endpoint of space identification. One great advantage of this device is that, it allows a slow advancement of the needle with both hands making a more accurate space identification possible (**Figure 4**).

When inflated and connected to the Tuohy needle, Epidrum allows higher pressure changes due to the location of the epidural space to be differentiated from those due to smaller changes in the path through the different tissues of the patient [7].

5.EpiFaith© syringe: EpiFaith is a relatively new device used in identifying the epidural space by loss of resistance technique. When the operator attaches the syringe to the Tuohy needle, the spring is held in place by the locking mechanism (where the yellow ring on the piston meets the blue plunger). The operator then pushes the syringe plunger forward to engage the spring. The operator can now

**Figure 4.** *Epidrum©.*

#### **Figure 5.**

*EpiFaith© syringe (drawing provided by flat medical Inc. (Taipei City, Taiwan)).*

advance the needle with two hands braced against the back. When the Tuohy needle tip enters the epidural space and there is a loss of resistance, the piston advances, and the yellow is visible. The piston moving forward, and the appearance of the yellow color are indicators of a loss of resistance [8] (**Figure 5**).

It is a device that ensures the Touhy needles comes to an abrupt halt with the pressure change in the epidural space. EpiFaith is mechanically driven and reduces the risk of accidental dural puncture.

*Perspective Chapter: Epidural Administration – Various Advances in Techniques DOI: http://dx.doi.org/10.5772/intechopen.108642*

While most of the methods described earlier depend on loss of resistance to air (which could introduce air to cause patchy blocks), Evron et al. demonstrated the relevance of loss of resistance to lidocaine which could best be described as loss of resistance to fluid [11]. The advantage of Evron et al. technique added more value in which dilutional factor with saline is circumvented rather synergistic to other local anesthetics administered into the epidural space.

#### **4. Methods of epidural administration**

Various methods have been advanced in carrying out epidural administration in clinical practice. Each of these methods is unique in its own way. The purpose of epidural administration could be short term or long term; depending on the need of the patient or the purpose for which it is administered. Epidural administration of medications can be effected through:

a.Manual (bolus) injection

b.Delivered by a machine

There are ways in which the administration can be conducted:

#### **4.1 Single shot epidural administration (SSEA)**

Single shot epidural injections, involves injecting a single dose of a drug. It eliminates the risk associated with epidural infusion through an indwelling catheter, such as restricting mobility limited options for anticoagulant therapy, injections and also for steroid injections. It is frequently used in management of radiculopathies [12]. This technique does not require the retention of an epidural catheter. While single-shot epidural administration may be ideal in some settings, the incidence of complications has been argued to be the same with the use of continuous epidural with use of a catheter. However its application is well out of place in modern labor analgesia practice. It is quite difficult to accurately quantify and qualify the adequacy of sensory level of analgesia following a single-shot. The use of a single-shot is in favor of epidural administration of steroids for radicular pain and others [13].

#### **4.2 Continuous epidural administration (CEA)**

Continuous epidural administration can be carried out with the use of either a volumetric pump or syringe pump. Each of these devices works differently. While the volumetric pump allows a calculated dose of medication in an infusion bag to flow through the epidural catheter at a predetermined rate, the syringe pump delivers a calculated dose of medication through a syringe and catheter at predetermined rate to the patient. Continuous epidural infusions offer a safety advantage over intermittent epidural injections because peak and trough levels of the analgesic agent are avoided.

Continuous epidural analgesia is commonly used for labor analgesia, postoperative pain control after thoracic, abdominal, lower extremity, and rarely, upper extremity surgeries. An infusion pump can be used to carry out epidural administration of medications. This device is commonly used in areas such as obstetrics to deliver medications (e.g., bupivacaine or other controlled substances) for maintenance of analgesia during labor.

#### *4.2.1 Infusion or volumetric pump*

This plays an important role in postoperative pain relief. It requires repeated injections or continuous infusion of local anesthetic solutions, using a volumetric pump, capable of delivering continuous and very specific amounts of fluid at either a slow or fast rate, with the presence of an indwelling catheter. The initial dose establishes the extent of analgesia and continuous infusion preserves it. It is associated with the risk of misplacing the catheter and infection [14]. However, a primary safety concern with epidural volumetric infusion pump is the risk of delivery through an incorrect

**Figure 6.** *A volumetric pump - Infusomat® P (B Braun).*

route of administration, which can happen when epidural infusions are mixed with intravenous infusions. Infusing medications intended for epidural delivery through intravenous sites or vice versa can be detrimental (**Figure 6**).

#### *4.2.2 Syringe pump*

The syringe pump can be used to deliver a calculated dose and rate of a medication into the epidural space through an epidural catheter (**Figure 7**).

The pump maintains a steady stream of flow of the medication administered without the patient's input.

#### **4.3 Combine spinal epidural administration (CSEA)**

Epidural administration can be achieved through the use of a combined spinal epidural technique. The epidural component of this procedure is through the placement of catheter into the epidural space [15]. The medications to be administered can be done through the use of an infusion (volumetric) or syringe pump.

#### **4.4 Patient controlled epidural administration (PCEA)**

The patient-controlled epidural analgesia (PCEA) technique has been recently set up as a preferred mode of epidural drug delivery and used widely. The development of PCEA allows patients to superimpose a limited volume of bolus dosing on an already established continuous infusion (**Figure 8**).

It has been found that patients with PCEA require less local anesthetic than patients with continuous epidural administration, to achieve a similar quality of epidural analgesia [16]. To forestall overdosing, the patient controlled pump is incorporated with a lockout mechanism which prevents repeated self-dosing within a given time interval.

#### **4.5 Computer integrated patient-controlled epidural injection (CIPCEA)**

Computer-integrated patient-controlled epidural analgesia (CIPCEA) is a novel epidural delivery system programmed to analyze the pharmacologic agent use across the last hour and adjusts the background infusion rate according to an algorithm [17] (**Figure 9**).

**Figure 7.** *P2000 syringe pump (IVAC®).*

#### **Figure 8.**

*Patient-controlled syringe pump SP-14S (aitecs©).*

#### **Figure 9.**

*Computer integrated patient controlled epidural pump (first generation computer integrated infusion pump set-up using an IBM Thinkpad laptop (IBM, USA) connected to a modified syringe pump (IVAC P700, Alaris, UK).*

This novel method of epidural drug injection automatically adjusts the injection rates based on the patients need for analgesia [18]. When compared with the conventional patient controlled injection, there was more patient satisfaction and less local anesthesia use in the CIPCEI group [18].

#### **4.6 Programmed intermittent bolus epidural injection (PIEBA)**

Programmed intermittent epidural bolus (PIEB) is a new way of injecting local anesthetic agents into the epidural space through an epidural catheter at fixed time intervals [19].

This is an automated method of administering boluses of local anesthetic solution into the epidural space at fixed time intervals. It has been described as a method that works perfectly well with patient-controlled epidural administration (PCEA) [16].

*Perspective Chapter: Epidural Administration – Various Advances in Techniques DOI: http://dx.doi.org/10.5772/intechopen.108642*

The combination of methods prolongs the duration of analgesia, reduces motor block, lowers incidence of breakthrough pain, and reduces local anesthetic consumption compared to continuous epidural injection [20]. However, it remains unclear what is the optimal PIEBA dosing regimen.

#### **5. Conclusion**

Epidural administration is a valuable tool in clinical practice. It has been used in various management or treatment of pain such as postoperative, labor analgesia, steroid administration, injection of platelet-rich plasma concentrate and other needs in clinical medicine. More researches are still on in exploring other ways the epidural space can be beneficial in clinical practice.

#### **Author details**

Sotonye Fyneface-Ogan\* and Fiekabo Ogan-Hart Obstetric Anaesthesia Unit, University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[4] Fyneface-Ogan S. Epidural space localization: A novel a slingshot approach. African Journal of Anesthesia and Intensive Care. 2014;**14**:1-5

[5] Fyneface-Ogan S, Mato CN. A clinical experience with epidural balloon in the localisation of the epidural space in labouring parturients. Nigerian Quarterly Journal of Hospital Medicine. 2008;**18**:166-169

[6] Riley ET, Carvalho B. The Episure™ syringe: A novel loss of resistance syringe for locating the epidural space. Anesthesia and Analgesia. 2007;**105**:1164-1166

[7] Sawada A, Kii N, Yoshikawa Y, Yamakage M. Epidrum(®): A new device to identify the epidural space with an epidural Tuohy needle. Journal of Anesthesia. 2012;**26**(2):292-295

[8] Athar MW, Guo N, Ortner C, Carvalho B, Abir G, Riley ET. An observational pilot study of a novel loss of resistance syringe for locating the epidural space. International Journal of Obstetric Anesthesia. 2021;**47**:102984. DOI: 10.1016/j.ijoa.2021.102984

[9] Lechner TJ, van Wijk MG, Maas AJ, van Dorsten FR, Drost RA, Langenberg CJ, et al. Clinical results with the acoustic puncture assist device, a new acoustic device to identify the epidural space. Anesthesia and Analgesia. 2003;**96**:1183-1187

[10] Carotenuto B, Micco A, Ricciardi A, Amorizzo E, Mercieri M, Cutolo A, et al. Optical guidance systems for epidural space identification. IEEE Journal of Selected Topics in Quantum Electronics. 2017;**23**:371-379

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[13] Patel K, Chopra P, Upadhyayula S. Epidural Steroid Injections. Treasure Island (FL): StatPearls Publishing; 2022

[14] Elsharkawy H, Sonny A, Chin KJ. Localisation of epidural space; a review of available technologies. Journal of Anaesthesiology Clinical Pharmacology. 2017;**33**(1):16-27

[15] Ueda K, Ueda W, Manabe M. A comparative study of sequential epidural bolus technique and continuous epidural bolus technique and continuous epidural infusion. Anaesth. 2005;**103**(1):126-129

[16] Sng BL, Woo D, Leong WL, Wang H, Assam PN, Sia AT. Comparison

#### *Perspective Chapter: Epidural Administration – Various Advances in Techniques DOI: http://dx.doi.org/10.5772/intechopen.108642*

of computer-integrated patientcontrolled epidural analgesia with no initial basal infusion versus moderate basal infusion for labor and delivery: A randomized controlled trial. Journal of Anaesthesiology Clinical Pharmacology. 2014;**30**:496-501

[17] Lim Y, Sia AT, Ocampo CE. Comparison of computer integrated patient controlled epidural analgesia vs. conventional patient controlled epidural analgesia for pain relief in labour. Anaesthesia. 2006;**61**(4):339-344

[18] Kim YJ, Lee DK, Kwon HJ, et al. Programmed intermittent epidural bolus versus continuous epidural infusion in major upper abdominal surgery: A retrospective comparative study. Journal of Clinical Medicine. 2021;**10**:5382. DOI: 10.3390/jcm10225382

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### **Chapter 2** Epidural: Loss of Resistance

*Prashanth Jagadeesha Prabhu*

#### **Abstract**

The epidural space is present above the dura also called as extradural space. This space contains spinal nerve roots and other contents with Batson's venous plexus. The lumbar epidural space is more than atmospheric pressure. Hence, one of the hypothesis for loss of resistance (LOR) during epidural is the loss of pressure exerted by dense ligamentum flavum. There are many methods to find the loss of resistance (LOR) technique. Two most common methods followed are loss of air technique and loss of saline technique. The recent advances speak about epidural waveform analysis for correct position of epidural catheter which is helpful in labor analgesia.

**Keywords:** epidural, loss of resistance, saline, air, methods, pressure

#### **1. Introduction**

The epidural needle (also known as extradural space or peridural space) pierces the skin, subcutaneous tissue, supraspinous ligament, interspinous ligament, ligamentum flavum, and finally epidural space (EDS). The failure rate of lumbar epidural is 27% and thoracic epidural is 32% [1].

#### **2. History of origin of loss of resistance to epidural space**

In 1921, Sicard and Forestier described loss of resistance (LOR) using lipiodol. Lipiodol is a chemical compound with 40% iodine with vegetable oil or poppy seed oil [2].

In 1928, Heldt and Moloney attempted to check the epidural pressure with spinal puncture needle with stopcock. They attached the manometer to the stopcock to measure the pressure. A negative pressure of 1 to 18 mm of mercury was recorded by the manometer once the needle was pushed deeper to the ligamentum flavum [3].

#### **3. Different methods available for the loss of resistance**

Various methods are described for epidural loss of resistance.

#### **3.1 Classification based on type of sensation appreciated**

Three categories of LOR have been described as:

The other classification of various methods to identify EDS (epidural space).

#### **3.2 Based on level or position of needle and epidural space**

Three categories are described:

Guiding the needle to EDS.

Identifying entry into epidural space (modifications of the loss of resistance technique).

*Epidural: Loss of Resistance DOI: http://dx.doi.org/10.5772/intechopen.109947*

Confirm catheter location in epidural space.

#### **3.3 The detection of epidural space can also be classified as two types: Subjective and objective types**

The subjective type can be subdivided into two types—human-based subjective type and equipment-based subjective type.

The objective type can be subdivided into two types—equipment-based objective type and ultrasound-based objective type.

#### *3.3.1 Human-based subjective type epidural space detection*

	- 1.Acoustic puncture assist device (APAD)
	- 2.LOR syringe with fluoroscopy
	- 3.EpiFaith syringe
	- 4.Episure autodetect syringe
	- 5.Epidrum
	- 6.Epidural balloon
	- 7.Electrocardiography (ECG)-guided system
	- 8.Drip infusion method
	- 1.Epidural waveform analysis
	- 2.CompuFlo
	- 3.Epidural stimulation test
	- 4.Epidurography
	- 5.Near-infrared tracking system
	- 6.Epiduroscope
	- 1.Ultrasonography.
	- Guidance positioning system for regional anesthesia (SonixGPS)
	- Three- and four-dimensional real-time ultrasound
	- Preprocedure 3D high-resolution images
	- Machine vision
	- Acoustic radiation force impulse (ARFI)

2.Doppler method.

#### **4. Human-based subjective-type epidural space detection**

#### **4.1 Loss of air**

It is the oldest and most common method followed for the loss of resistance technique to detect the epidural space [6]. This technique is done by filling air into syringe and connected to epidural needle to detect the loss of resistance.

Some complications are observed by the use of loss of resistance to air. They are pneumocephalus, air embolism, insufficient analgesia, delayed onset, higher incidence of dural puncture, nerve root compression, and subcutaneous emphysema [7].

#### **4.2 Loss of fluid**

Dogliotti described the loss of fluid technique in epidural space. He described that while advancing the needle by exerting the pressure on the piston of the syringe. Once this needle enters the epidural space, there is the sensation of needle slipping, simultaneous disappearance of resistance to injection, and the pressure felt on the piston of the syringe will disappear. He with his team also described about polyethylene catheter insertion to epidural space [8].

#### **4.3 Saline with air bubble**

Odom devised this method by attaching the capillary glass tube with air bubble and fluid. He modified the capillary method of saline with air bubble of 2 ml. He said that the movement of this air bubble to the needle indicates epidural space, and the movement of the air bubble away from the needle indicates subarachnoid space (dural tap) [9].

The fluid LOR does not provide the same feel as air for appreciating the LOR.

#### **4.4 Lidocaine**

2–3 ml test dose of lignocaine 1–2% confirms the epidural space. If the lidocaine is administered to subarachnoid space, there is be sudden onset of weakness in bilateral lower limbs, and it does not occur when it is administered into epidural space. This property is used as test dose to confirm the epidural space.

#### **4.5 KSMM (The combined plunger pressure-manometer method)**

It is a satisfactory alternative for the loss of resistance technique [10].

#### **4.6 BiP test (Bidigital pressure test)**

It is a simple procedure where pressures of two fingers are used to feel the LOR for epidural [11]. It is described that pressures of two fingers are adequate to feel the epidural space.

#### **4.7 Use of hanging drop**

Alberto Gutierrez discovered the hanging drop technique in February 1933. He was searching for epidural space with LOR technique with fluid. Due to stiff resistance, he removed LOR syringe and noted a small drop of liquid hanging at the tip of the needle. As he advanced the needle, the drop suddenly disappeared or moved inside the epidural space due to negative pressure of the epidural space [12].

#### **4.8 CSF (Cerebral spinal fluid) ceased to drip**

A method described by Sebrechts describes to do a dural tap in the beginning by inserting the needle into the subarachnoid space. Later, the needle is withdrawn until CSF ceased to drip to locate the epidural space [6].

#### **4.9 Sterile water injection**

Lund used 5 cc syringe filled with distilled water for epidural space identification. The distilled water causes burning pain if the patient is awake, and in asleep patient it causes slight movement [13]. It is due to irritation caused by sterile water in epidural space.

#### **4.10 Loss of guidewire resistance (LOGR, epidural space finder)**

The guidewire is used instead of air in the LOR technique. When the needle goes through the ligamentum flavum, there was constant rotation of dials on both sides leading to resistance of guidewire. Once the needle entered the epidural space, the dial lost the resistance and the guidewire moved a few centimeters into the epidural space [14].

#### **4.11 Membrane in syringe technique**

In this technique, a plastic membrane is placed in the middle of the syringe, dividing it into two compartments. The distal compartment of syringe has nozzle and is filled with saline. The proximal part of the syringe has plunger and is filled with air. Once this enters, the epidural space wrinkling of the plastic membrane is seen which can be appreciated by the loss of air. This technique also avoids injection of air into the epidural space. Even sometimes due to no appreciation of loss of resistance, the epidural space is identified by visible wrinkling of the membrane [15].

#### **4.12 Epidural Queckenstedt test**

Compression of bilateral internal jugular veins lead to increased subarachnoid pressures and increased epidural pressure which is used to confirm epidural puncture in this test [16].

#### **4.13 Cold test**

The injection of local anesthetic into epidural space gives a cold sensation in the back, and it is called as the cold test [17].

#### **4.14 Hissing sound**

In loss of resistance to air technique, once the needle enters the epidural space the air rushes into the epidural space. This is detectable on a stethoscope attached to epidural needle and audible as hissing sound [18].

#### **4.15 Second needle method**

After first needle LOR is obtained, the second needle LOR is obtained in the adjacent intervertebral space. If both these needles are in epidural space, 5 ml of rapid injection of normal saline from one needle will lead to fluid leakage from the other needle called the second needle method [19].

Current scientific evidence:

be always cautious of the quantity of air pushed in epidural space and its placement [22].

Limitations and disadvantages of some popular techniques

There has been some explanation by MRI studies for false loss of resistance. Supraspinous ligament and interspinous ligament in lumbar region are biconcave axially. These gaps lead to deposition of anterior fat giving false loss of resistance [23].

The other causes of false-positive loss of resistance are as follows:

#### **5. Equipment-based subjective-type epidural space detection**

These methods use equipments to detect the loss of resistance. It is not definitive that the loss of resistance is in epidural space. It is therefore highly subjective in the detection of epidural space.

#### **5.1 Acoustic puncture assist device (APAD)**

It documents pressure throughout the procedure of epidural. It provides real-time auditory and visual displays of pressure waveforms. It simultaneously uses three senses: hear (auditory signal), see (pressure and auditory graph on the screen), and touch (LOR from the needle) [24].

#### **5.2 LOR technique with fluoroscopy**

It is done in the prone position. Once the needle reaches L5-T1 interlaminar foramen, fluoroscopy of AP (anteroposterior) is done to confirm the placement. When LOR is done, lateral view of the fluoroscopy is done [25]. The disadvantage of this technique is patient needs to be put in prone position to undergo fluoroscopy.

#### **5.3 EpiFaith syringe**

The EpiFaith syringe has a spring-loaded plunger with the syringe. On the loss of resistance, the syringe moves by itself thus showing the epidural space [26].

#### **5.4 Episure autodetect syringe**

It is a spring-loaded loss of resistance syringe with a coaxial compression spring within a LOR syringe. This syringe gives constant pressure when it is being advanced. Hence, the operator can use both his hands in advancing the needle [12]. To minimize the false loss of resistance, the episure syringe is attached to the needle once its tip is in the interspinous ligament as this does not detect epidural space, but it detects only the loss of resistance [27].

#### **5.5 Epidrum**

It contains a small drum with a diaphragm on one of its sides. The device is placed between Tuohy needle and syringe for epidural placement. On penetration of epidural space, there is sudden collapse of the diaphragm giving visual evidence confirming the loss of resistance. It takes less attempts and shorter time in comparison with standard LOR [28].

#### **5.6 Epidural balloon**

A small inflated balloon is attached to the hub of the epidural needle, while the epidural needle is being inserted. On obtaining the epidural space, the balloon collapses due to negative pressure [29]. A Y-shaped connector is attached to the epidural needle where the one end is having the balloon and the other end is attached to the syringe for charging the balloon. The balloon collapse on entering the epidural space is faster than traditional LOR giving a visual evidence of loss of resistance [30].

#### **5.7 Electrocardiography (ECG)-guided system**

In this system, the epidural tip is having or contains one of the ECG lead. Another surface electrode is positioned at desired dermatomal level. Once this ECG enabled epidural catheter reaches the desired segment, it matches with the reading of the surface electrode [31]. It confirms the needle entry into respective dermatomal level.

#### **5.8 Drip infusion method**

It combines method of LOR with drip infusion for confirmation of the epidural space. It identifies the true epidural space by LOR and later with fluid dripping present. In pseudo or false LOR, there is no fluid dripping [32].

Current scientific evidence:

Limitations and disadvantages of some popular techniques

The advantage of ECG-guided epidural catheter is that it can be used in the presence of local anesthetic and neuromuscular blocking agents. This technique helps to match the vertebral level of particular dermatome but does not confirm its location in epidural space.

#### **6. Equipment-based objective-type epidural space detection**

These are the techniques or methods which take the help of equipments and identify the epidural space accurately most of the times.

#### **6.1 Epidural waveform analysis**

In the epidural pressure waveform, there is a drop in pressure once the catheter enters the epidural space. Epidural space pressure waveform and computed tomography cathetergram are helpful in identifying the epidural space and location of epidural catheters. It is obtained by transducing an epidural catheter. The pressure changes observed on epidural waveform when the needle went through ligamentum flavum is around 82 25 mmHg. This pressure dropped to 6.5 11.6 mmHg once the needle entered the epidural space [35]. The quantity of saline required for epidural waveform analysis is 5 ml.

The epidural pressure waveform analysis has reported 81% sensitivity, 100% specificity, 100% positive predictive value, and 17% negative predictive value [36].

#### **6.2 CompuFlo**

The CompuFlo epidural instrument is a computer controlled drug delivery system that can precisely measure the pressure of human tissues in real time at the tip of the needle. It gives real time exit-pressure data at the needle tip. Both visual and audio graphic of exit pressure is provided. With CompuFlo, the needle entry into the ligamentum flavum increase pressure and audible tone. Once it enters the epidural space there is a big drop in pressure and audiotone. A drop in pressure for more than 5 seconds confirms entry into epidural space [37, 38].

CompuFlo helps in identification of true loss of resistance by sudden and sustained drop (more than 5 seconds) in pressure (greater than 50% of maximum pressure) and pitch of audible tone with formation of low and stable plateau pressure. In case of false LOR any one of the above is not achieved. If the pressure increases after drop in pressure it is a false LOR [39].

#### **6.3 Epidural stimulation test**

It involves electrical stimulation of nerves passing through the epidural space. Motor or sensory response to stimulation of 1–10 mA indicates epidural location of catheter. Stimulation <1 mA happens when the catheter is in subarachnoid position, subdural space, or close to nerve root [40].

#### **6.4 Epidurography**

It is obtaining fluoroscopy of contrast dye administered through epidural catheter. Typical epidural spread can be appreciated on fluoroscopic image. Equipment required and radiation risks are the disadvantages of this technique [41].

#### **6.5 Near-infrared tracking system**

A fiberoptic wire is placed in an epidural catheter which emits infrared signal picked up by infrared camera. This infrared tracking system helps in the identification of the epidural space. In this technique, the signal is poor in obese patients, and when catheter passes under the lamina making it is difficult to track the epidural space [42].

#### **6.6 Epiduroscope**

It is a fiberscope or a camera which is advanced through the 18-guage Tuohy needle into the epidural space. The outer diameter of this scope is 0.8 mm [43]. This epiduroscope gives the visualization of the epidural space.

#### Current scientific evidence

Attempts were made to check the epidural pressure. It was found that at T3–T5 level, the median epidural pressure was 1 mmHg (1 to 4.5 mmHg). The epidural pressure at T7–T10 level is 4 mmHg (2 to 7.8 mmHg). The subatmospheric epidural pressure is higher at mid-thoracic area in comparison with lower thoracic area [44]. The lumbar epidural pressure is greater than atmospheric pressure when referenced to zero at the dorsal spine level [45].

Limitations and disadvantages of some popular techniques

The CompuFlo can be used to localize the epidural space, but it does not decrease the overall catheter failure rate or accidental dural puncture rate. It does not help in the identification of midline or guide the trajectory of the epidural needle [46].

The epidural pressure waveform will not aid in the detection of subarachnoid, intravascular, or subdural catheter misplacement [47]. Hence, it is not cent percent effective in the confirmation of epidural space.

The disadvantages of epidural stimulation are that it becomes ineffective on the administration of local anesthetic, neuromuscular blocking agents, and in preexisting neuromuscular disease. It becomes ineffective in those conditions where the nervous system is affected.

#### **7. Ultrasound-based objective-type epidural space detection**

#### **7.1 Ultrasonography**

Two methods are used.

#### *7.1.1 Preprocedural ultrasound scanning*

A handheld ultrasound device for epidural identification—A wireless ultrasound device is used to limit the storage space for the ultrasound equipment. The software is programmed to calculate the depth of the epidural space. Horizontal and vertical lines are drawn from the midpoint to the probe at each inter spinous space. Later, the ultrasound device is kept aside. Using the marked lines, the epidural needle is inserted to the depth achieved by the ultrasound earlier to get the epidural space. The success of up to 87% has been achieved for the first pass of epidural needle to identify the epidural space by the ultrasound method [48].

#### *7.1.2 Real-time ultrasound guidance*

Though it is real-time placement of epidural catheter, two operators are considered necessary for real-time ultrasound guidance [49]. Some have reported that single person technique is possible by in-plane method, and it requires a lot of expertise in doing the same. There is also risk of ultrasound gel entering the epidural space [50].

Different types of ultrasound modalities are used to help localize the epidural space.

i. Guidance positioning system for regional anesthesia (SonixGPS).

This uses an electromagnetic motion tracking system which helps in determining the position of the needle. It is more useful in out-of-plane approach [51].

ii. Three- and four-dimensional real-time ultrasound.

Three- and four-dimensional real-time ultrasound has shown to help in regional anesthesia [52]. Certain difficulties are present in 3D/4D ultrasound images. They are varying bony shadows and artifacts due to complex anatomy of the spine. There are also problems with poor resolution, poor needle visibility, and reduced frame rate. Hence, it requires a high skill to perform the needle insertion into the epidural space.

iii. Preprocedure 3D high-resolution images.

The preprocedure three-dimensionsl high-resolution images are constructed and later used in real-time 2D ultrasound image. This helps in the point of insertion of needle, trajectory of the needle, and depth of epidural space, making it more easier in getting the epidural space.

iv. Machine vision.

The machine vision is a form of artificial intelligence where computer is helping to recognize images. It compares with previous stored data, and once familiar structures are recognized, they are pointed out by ultrasound image [53]. This artificial intelligence helps and gives clues to direct the epidural needle in the right direction and right depth. It helps by correlating the present ultrasound image with previous stored images.

v. Acoustic Radiation Force Impulse (ARFI).

In the acoustic radiation force impulse (ARFI), the images are derived from differences in the mechanical properties of tissue rather than acoustic properties. It is used to know the tissue structural and mechanical properties. In ARFI imaging plane, if imaging needles are out of required plane, the local stiffening effect of the needle can be visualized within ARFI imaging plane, thus helping in needle visualization [54].

#### **7.2 Doppler method**

The epidural needle is connected to a Doppler probe which is connected to a speaker and a paper recorder. On entry to epidural space through loss of resistance, "whoosh" sound is heard followed by spontaneous drop in Doppler flow tracing [55]. The appreciation of this sound helps in the identification of the epidural space.

Limitations and disadvantages of some popular techniques

The difficulty with real-time two-dimensional ultrasound is tracking of needle. From entry to epidural space is visualization of needle, or needle tip is difficult. This can be taken care with the help of needle tracking and navigation tools.

Needle visibility is a problem with ultrasound methods. Usually 2D B-mode ultrasound guidance is used for needle entry guidance to epidural space. The needle visibility is difficult when insertion angle is too steep, difference between imaging plane and needle plane and small needle gauge.

#### **8. Future of epidural space detection**

Raman spectroscopy has shown unique spectrum for all paravertebral and neuraxial tissue layers in porcine tissues [56]. Further studies of Raman spectroscopy is required on human subjects. If proved or invented, unique spectrum of Raman spectroscopy can be used to identify the epidural space.

Color flow Doppler function is being used to visualize the flow in epidural space on the injection of normal saline or air (1 ml over 1 second) [57]. Higher skills training is required, and it might require a long learning curve for expertise.

CompuFlo or technology built on the same with real ultrasound guidance could be the future instrument or technique of choice for difficult epidural.

Fiber Bragg grating (FBG) sensor for loss of resistance—This uses a novel soft system (SS) based on one fiber Bragg grating sensor (FBG) which is present in a soft polymeric matrix for LOR detection [58].

Ultrasound—Embedded needle is used for the identification of epidural space, and placement of catheter in real time with axial resolution of 0.15 mm has been tried on porcine models [59]. Further human trials are required to evaluate the effectiveness on humans.

Bioimpedance—Different tissues have different electrical impedance. This property helps to distinguish different types of tissues. Epidural space has higher fat content compared to nearby structures. This property could be utilized by bioimpedance in future to detect epidural space [60].

Optical spectroscopy—This method is tested on animal models. The needle is customized with optical fibers integrated into the cannula. The optical spectra (visible and near-infrared wavelength) are obtained at different depths. The estimates of blood and lipid volume fractions are determined. The lipid fractions obtained from epidural space were in the range of 1.9- to 20-fold higher than muscle, and epidural vein has high blood volume fraction [61].

Optical coherence tomography (OCT)—This is a type of B-mode ultrasonography using light reflection. This technology uses the light reflected to determine the depth of penetration to 2–7 mm to create the images of the tissue. This technology has helped to avoid neural damage in animal studies [62].

Due to reduced opportunities and to mitigate medical errors, simulation training for technical skills will help the trainees. To bridge the requirements and resources, multiple simulators from different manufactures are available in the market.

#### **9. Conclusion**

It has been more than 100 years since the discovery of LOR in epidural space, and we have not been able to find an ideal method to detect LOR space which has 100% specificity and 100% sensitivity and is safe and user-friendly. Research for better methods are still required to discover an ideal LOR instrument for the epidural space.

#### **Author details**

Prashanth Jagadeesha Prabhu Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### Section 2


**5. Expression of early genes**

At the time the virus reaches the nucleus, the template DNA for transcription as well as proteins of the virion that are carried over and may activate transcription are at their lowest levels. Therefore, the success of the infection depends on the ability of the virus to efficiently redirect the cellular system to express early genes encoded in its genome. Baculovirus DNA is infectious without any accompany protein, as proved by the infection that follows after transfection of permissive cells with viral DNA. This indicates that baculovirus early promoters are respon‐ sive to the RNA pol II and accordingly, their structural organization resembles that of the host genes which are transcribed into mRNAs.

Promoters of baculovirus early genes consist in a core region and regulatory proximal sequences that may be recognized for specific binding of transcription factors from either the host or the virus. The core promoter includes two characteristic elements: a TATA-box-like sequence and a transcription initiator (INR), although one or both are absent in some early promoters [12]. The TATA box is the site for assembly of the preinitiation transcription complex by first binding of TATA binding protein (TBP). After the RNA pol II is recruited to the complex, transcription starts about 30 nucleotides downstream of the position of the TATAbox. The INR determines the starting site for transcription (nucleotide +1 of the primary transcript), and ensures proper initiation when there is no TATA-box present. CAGT is the most conserved INR sequence motif in baculovirus early promoters. Other activating sequen‐ ces can be found either upstream of the core promoter or downstream, in the 5´UTR of the regulated gene.

Besides the sequences within the promoter region that modulate expression of a gene through the binding of regulatory proteins, there are sequences that enhance transcription from promoters even if they are located at a long distance. In baculoviruses there are non-coding regions known as homologous regions (*hr*) that play the role of enhancers [13] (see below).

Baculovirus early genes can be subdivided into two categories: immediate-early (*ie*) and delayed-early genes. Expression of *ie*-genes does not require viral factors, whereas the transcription of delayed-early genes was shown to need activation by *ie*-genes in transient expression assays. The major transactivator of AcMNPV early genes is the product of *ie1*, a gene that is present in all lepidopteran baculoviruses [14].

Other *ie-*genes known to regulate the expression of early genes are *ie2* and *pe38*. *ie2* is conserved only in group I alphabaculoviruses, one the two phylogenetic lineages in which members of this genus can be separated. In transient expression experiments it was determined that *ie2* increases IE1-mediated transactivation of early promoters when *ie1* is present at low concentrations [15]

#### **5.1. Immediate early transactivator IE1**

**Figure 1.** Kinetics of transcription of baculovirus genes. The time courses of steady-state level of transcripts (y axis) of the three AcMNPV temporal classes of genes, in Sf21 cells, are shown schematically. Solid lines represent mRNAs in wild-type (wt) infection; dotted lines represent idealized transcriptional profiles in infections in which a virus gene re‐ quired for either DNA replication or late transcription was silenced by RNAi (denoted by "-"). Early genes are transcri‐ bed by the host RNA polymerase II before virus DNA replication, which initiates 6 to 9 hours post infection (hpi). Transcripts of early genes are detectable within 1 hpi, reach a maximum between 6 to 12 hpi and diminish thereafter (shutoff). Transcription of late and very late genes depends on viral DNA replication and is performed by a virus-en‐ coded RNA polymerase. Transcription of late genes begins with the onset of DNA replication and continues mainly up to 24 hpi, while transcription of very late genes bursts around 18 hpi and continues through 72 hpi. The figure shows that late/very late gene transcription is abolish by silencing *p47*, a gene that encodes a subunit of the RNA polymer‐ ase, which is essential for the activity of the enzyme. A similar effect is shown as consequence of silencing *lef3*, a gene essential for virus DNA replication, since DNA replication is required for transcription of late/very late genes. However, the effects of silencing these genes on expression of early genes are different. When *p47* is silenced, early gene tran‐ scription declines as in wild-type infection; in contrast, silencing of *lef3* blocks the reduction of transcription, indicating that DNA replication, rather than late transcription, is a primary determinant of the shutoff of early genes (adapted

60 Current Issues in Molecular Virology - Viral Genetics and Biotechnological Applications

from [65]).

AcMNPV IE1 is a 582 aminoacids long protein exhibiting general characteristics of transcrip‐ tion factors (figure 2). It has a modular organization with domains associated to different functions: dimerization, nuclear import, DNA-binding, transactivation and replication [16-17]. Dimer formation is required for nuclear localization since the protein mutated in the dimeri‐ zation domain cannot be imported into the nucleus [18]. IE1 transactivates early promoters including its own. Two mechanisms are postulated by which IE1 is capable of activating an early promoter: one independent and one dependent on DNA-binding. In the first one, IE1 activates transcription by interaction with cell factors recruited to the promoter regulatory regions. In the DNA-binding-dependent mechanism, the activation depends on binding of IE1 to *hr* sequences which function as enhancers. The *hrs* contain a variable number of imperfect palindromic repeats in tandem, separated by non-palindromic sequences. The palindromes are conserved within a genome but differ widely between genomes. In AcMNPV the imperfect palindrome consensus sequence has a length of 28 nucleotides with a central *Eco*RI site. According to the current knowledge, each subunit of the IE1 dimer interacts with a corre‐ sponding hemipalindrome during binding to an *hr*. Binding of IE1 to the enhancer increases the effective concentration of IE1 molecules able to interact with cellular factors in the promoter region. It was found that *hrs* also bind cellular factors in sites overlapping palindromic repeats and within interpalindromic regions [19-20]. *Hrs* are enriched in sequence motifs similar to cAMP and TPA response elements known to interact with transcription factors of the bZIP family. This is consistent with the ability of *hrs* to enhance transcription from baculovirus early promoters even in the absence of viral factors (see [21]for a review).

It has been reported that AcMNPV IE1 down-regulates the expression of certain genes. Promoters of these genes contain a sequence motif similar to one half of a typical *hr* palindrome which still functions as a target for IE1 binding; however, IE1 bound to this sequence is no longer able to promote activation, instead it functions as a repressor [22].

IE1 is the only known baculoviral gene that is expressed as part of a product of alternative splicing designated IE0. Compared to IE1, AcMNPV IE0 contains 54 additional aminoacids at its N-terminus. Both protein species are required for an efficient infection, although each one is dispensable given the other is present [23].