Tips and Tricks in Tips and Tricks in Laparoscopic Dissection Laparoscopic Dissection

of Adhesionsof AdhesionsGeorge Khoury, MDGeorge Khoury, MD

George Ferzli, MD, FACSGeorge Ferzli, MD, FACS

LUTHERANLUTHERANMEDICAL CENTERMEDICAL CENTER

SUNY DOWNSTATE SUNY DOWNSTATE MEDICAL CENTERMEDICAL CENTER

VeniceVeniceJuneJune 2005 2005

Historical PerspectivesHistorical Perspectives 1836 - Thomas Hodgkin: 1836 - Thomas Hodgkin:

Matted bowel at autopsy in patients with Matted bowel at autopsy in patients with tuberculous peritonitis tuberculous peritonitis

Lower abdominal adhesions in patients Lower abdominal adhesions in patients dying of pelvic sepsisdying of pelvic sepsis

1872 - Thomas Bryant (Guy’s Hospital, London)1872 - Thomas Bryant (Guy’s Hospital, London) Fatal small bowel obstruction from a band formed after removal of an Fatal small bowel obstruction from a band formed after removal of an

ovarian cyst ovarian cyst

1883 - Thomas’ Hospital (London)1883 - Thomas’ Hospital (London)William Battle (published in the William Battle (published in the Lancet)Lancet)

Thomas’s Hospital, London – the first account of a laparotomy for Thomas’s Hospital, London – the first account of a laparotomy for adhesive obstruction. The patient, a 43-year-old woman, had bilateral adhesive obstruction. The patient, a 43-year-old woman, had bilateral ovarian tumors removed 4 years earlier. She was admitted with intestinal ovarian tumors removed 4 years earlier. She was admitted with intestinal obstruction. Matted adhesions of terminal ileum in the region of the obstruction. Matted adhesions of terminal ileum in the region of the cecum were found at laparotomy and a terminal ileostomy was cecum were found at laparotomy and a terminal ileostomy was performed. Sadly, she died 3 weeks later.performed. Sadly, she died 3 weeks later.

Harold Ellis,CBE,FACS (Hon),FRCS, Harold Ellis,CBE,FACS (Hon),FRCS, JACSJACS vol 200, #5 May 2005 vol 200, #5 May 2005

Adhesion PathophysiologyAdhesion PathophysiologyA. Fibrin formation (peritoneal insult):A. Fibrin formation (peritoneal insult):Exposure to infection or intestinal contents; ischemia; irritation (sutures, glove powder,Exposure to infection or intestinal contents; ischemia; irritation (sutures, glove powder,gauze particles) abrasion; desiccation; overheating by lamps or irrigation fluid, etc.gauze particles) abrasion; desiccation; overheating by lamps or irrigation fluid, etc.

B. Fibrin gel matrix:B. Fibrin gel matrix: ‘‘‘‘Ground’’ through which mesothelial cells migrate and reepithelializeGround’’ through which mesothelial cells migrate and reepithelialize

C. Coalescence:C. Coalescence:Injured peritoneal surfaces come into apposition - form sticky fibrin bridges Injured peritoneal surfaces come into apposition - form sticky fibrin bridges Surgery reduces fibrinolytic activity (strands normally dissolve within days) Surgery reduces fibrinolytic activity (strands normally dissolve within days)

D. Proliferation of fibroblasts:D. Proliferation of fibroblasts:

Fibrinous matrix is infiltrated by fibroblasts which deposit collagen Fibrinous matrix is infiltrated by fibroblasts which deposit collagen Mesothelial cells migrate and form an layers on the surface of the adhesion Mesothelial cells migrate and form an layers on the surface of the adhesion

E. Ischemia and Hypoxia:E. Ischemia and Hypoxia:Tissue underlying the adhesion is relatively hypoxic and signals the initiation of Tissue underlying the adhesion is relatively hypoxic and signals the initiation of angiogenesis, resulting in a vascularized adhesionangiogenesis, resulting in a vascularized adhesion

Prevention of fibrin depositionPrevention of fibrin deposition

A.Fibrin formationA.Fibrin formation Use of citrate, heparin (topically and systemically)Use of citrate, heparin (topically and systemically)

Deaths from hemorrhage were reported in laboratory animals. Deaths from hemorrhage were reported in laboratory animals. Bleeding – even deaths, occurred in patients given intraperitoneal Bleeding – even deaths, occurred in patients given intraperitoneal heparin.heparin.

B. Removal of fibrin exudatesB. Removal of fibrin exudatesWash away or dilute fibrin using saline, hypertonic dextrose, pepsin, Wash away or dilute fibrin using saline, hypertonic dextrose, pepsin, trypsin, streptokinase, streptodornase and tissue plasminogen activatortrypsin, streptokinase, streptodornase and tissue plasminogen activator

C. Separation of surfacesC. Separation of surfaces Saline, Ringer’s, dextran, gelatine, olive oil, paraffin, silicones, plasma, Saline, Ringer’s, dextran, gelatine, olive oil, paraffin, silicones, plasma, lanoline, polyvinyl pyrrolidine, lanoline, polyvinyl pyrrolidine, Membranes – amnion, fish bladder, carp peritoneum, calf peritoneum, Membranes – amnion, fish bladder, carp peritoneum, calf peritoneum, oiled silk, silver or gold foil and free grafts of omentum; hyaluronic acid oiled silk, silver or gold foil and free grafts of omentum; hyaluronic acid and carboxymethyl cellulose membrane, more recently, icodextrin.and carboxymethyl cellulose membrane, more recently, icodextrin.

D. Inhibition of proliferationD. Inhibition of proliferation Antihistamines and steroidsAntihistamines and steroids

E. Prevention of ischemia and hypoxiaE. Prevention of ischemia and hypoxiaHyperbaric oxygen and heparinHyperbaric oxygen and heparin

Complications related to adhesionsComplications related to adhesions Chronic pelvic pain (20–50% incidence)Chronic pelvic pain (20–50% incidence)

Small bowel obstruction (30-60% incidence)Small bowel obstruction (30-60% incidence)

Infertility (15–20% incidence)Infertility (15–20% incidence)

Increase technical difficulties of subsequentIncrease technical difficulties of subsequentintraabdominal surgical procedures intraabdominal surgical procedures (reentry, peritoneal dialysis…)(reentry, peritoneal dialysis…)

High cost: In 1996 Medicare paid $ 3.22 billion for adhesion related High cost: In 1996 Medicare paid $ 3.22 billion for adhesion related complications.complications.

Laparoscopic adhesiolysis for Laparoscopic adhesiolysis for intestinal obstructionintestinal obstruction

Statistics:Statistics: Adhesions are leading cause of intestinal obstruction (30 to 60% of cases). Adhesions are leading cause of intestinal obstruction (30 to 60% of cases).

Data from the Scottish National Service revealed 280 readmissions (0.67%) Data from the Scottish National Service revealed 280 readmissions (0.67%) necessitating operative treatment for adhesive small-bowel obstruction in anecessitating operative treatment for adhesive small-bowel obstruction in acohort of 41,841 patients who underwent initial abdominal surgery 10 years cohort of 41,841 patients who underwent initial abdominal surgery 10 years before. before.

A review of 18,912 patients with open surgery found that 2.6% required A review of 18,912 patients with open surgery found that 2.6% required surgery for adhesive intestinal obstruction within 2 years. surgery for adhesive intestinal obstruction within 2 years.

Another study followed 2,708 laparotomies for an average of 14.5 months Another study followed 2,708 laparotomies for an average of 14.5 months and counted 26 cases (1%) that developed intestinal obstruction due to and counted 26 cases (1%) that developed intestinal obstruction due to postoperative adhesions within 1 year.postoperative adhesions within 1 year.

0.5 and 2.6% appear low but worldwide – results in a considerable number 0.5 and 2.6% appear low but worldwide – results in a considerable number of patients readmitted and re-operated on an emergency basis.of patients readmitted and re-operated on an emergency basis.

Fewer adhesions induced by laparoscopic surgery? CN Gutt, T Oniu, P Schemmer, A Mehrabi, Fewer adhesions induced by laparoscopic surgery? CN Gutt, T Oniu, P Schemmer, A Mehrabi, MW BuchlerMW Buchler Surg Endosc Surg Endosc (2004) 18: 898–906.(2004) 18: 898–906.

Can laparoscopy reduce adhesion formation?Can laparoscopy reduce adhesion formation?

A. Fibrin formation (peritoneal insult):A. Fibrin formation (peritoneal insult): Laparoscopy is thought to reduce trauma to the abdominal wall, intraabdominal Laparoscopy is thought to reduce trauma to the abdominal wall, intraabdominal operative site and organs, potentially reducing postoperative adhesion formationoperative site and organs, potentially reducing postoperative adhesion formation

B. Removal of fibrin exudates (matrix gel):B. Removal of fibrin exudates (matrix gel): Less tissue trauma and hemmorhageLess tissue trauma and hemmorhage

C. Separation of surfaces (coalescence ):C. Separation of surfaces (coalescence ):Early return of bowel activity and early ambulationEarly return of bowel activity and early ambulation

D. Inhibition of fibroblast proliferationD. Inhibition of fibroblast proliferation

E. Ischemia and Hypoxia:E. Ischemia and Hypoxia: COCO22 effect and high pressures may cause more adhesions? effect and high pressures may cause more adhesions?

Fewer adhesions induced by laparoscopic surgery? CN Gutt, T Oniu, P Schemmer, A Mehrabi, Fewer adhesions induced by laparoscopic surgery? CN Gutt, T Oniu, P Schemmer, A Mehrabi, M W BuchlerM W Buchler Surg Endosc Surg Endosc (2004) 18: 898–906(2004) 18: 898–906

Laparoscopic adhesiolysis for small bowel obstruction. Alexander Nagle, MD, Michael Ujiki, MD,Laparoscopic adhesiolysis for small bowel obstruction. Alexander Nagle, MD, Michael Ujiki, MD,Woody Denham, MD, Kenric Murayama, MD*Woody Denham, MD, Kenric Murayama, MD* The American Journal of Surgery The American Journal of Surgery 187 (2004) 187 (2004) 464–470464–470

Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomised Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomised controlled multi-centre trial D J Swank, S C G Swank-Bordewijk, W C J Hop, W F M van Erp, controlled multi-centre trial D J Swank, S C G Swank-Bordewijk, W C J Hop, W F M van Erp, I M C Janssen, HBonjer, J JeekelI M C Janssen, HBonjer, J Jeekel THE LANCET THE LANCET • Vol 361 • April 12, 2003• Vol 361 • April 12, 2003

Results of laparoscopic adhesiolysis Results of laparoscopic adhesiolysis for small bowel obstructionfor small bowel obstruction

Chosidow Chosidow et alet al: : Emergency laparoscopic adhesiolysis in 39 patients; Emergency laparoscopic adhesiolysis in 39 patients; 36% conversion rate compared with 7% in elective cases36% conversion rate compared with 7% in elective cases

Suter Suter et alet al: : Bowel diameter exceeding 4 cm is associated with an increased rate of Bowel diameter exceeding 4 cm is associated with an increased rate of conversion: 55% versus 32% (conversion: 55% versus 32% (P P 0.02) 0.02)

Leon Leon et alet al: : A documented history of severe or extensive dense adhesions is a A documented history of severe or extensive dense adhesions is a contraindication to laparoscopycontraindication to laparoscopy

Franklin:Franklin: 23 patients 13% conversion 23 patients 13% conversion

Strickland:Strickland: 40 patients 32.5% conversion 40 patients 32.5% conversion

Ibrahim:Ibrahim: 33 patients 33% conversion 33 patients 33% conversion

Laparoscopic adhesiolysis for small bowel obstruction. Alexander Nagle, MD, Michael Ujiki, MD, Laparoscopic adhesiolysis for small bowel obstruction. Alexander Nagle, MD, Michael Ujiki, MD, Woody Denham, MD, Kenric Murayama, MD*Woody Denham, MD, Kenric Murayama, MD* The American Journal of Surgery The American Journal of Surgery 187 (2004) 187 (2004) 464–470.464–470.

Reasons for ConversionReasons for Conversion Inability to identify origin of the obstruction (reduced working space Inability to identify origin of the obstruction (reduced working space

because of intestinal distension) is the most commonbecause of intestinal distension) is the most common

Inability to relieve obstruction because of unique anatomic features Inability to relieve obstruction because of unique anatomic features

Adhesions are too extensiveAdhesions are too extensive

Accidental bowel perforationAccidental bowel perforation

Bowel necrosisBowel necrosis

Causes not amenable to laparoscopic treatment (tumor, incarcerated Causes not amenable to laparoscopic treatment (tumor, incarcerated hernia)hernia)

Laparoscopic management of mechanical small bowel obstruction Are there predictors of success or Laparoscopic management of mechanical small bowel obstruction Are there predictors of success or failure? M Suter, P Zermatten, N Halkic, O Martinet, V Bettschartfailure? M Suter, P Zermatten, N Halkic, O Martinet, V Bettschart Surg Endosc Surg Endosc (2000) 14: 478–483.(2000) 14: 478–483.

Operating RoomOperating Room OR table – full tilt range (extreme positions may be necessary)OR table – full tilt range (extreme positions may be necessary)

Patient’s arms by side to allow the surgical team ample room Patient’s arms by side to allow the surgical team ample room

Two movable video monitors:Two movable video monitors:video monitor to the patient’s right positioned inferiorly at the hip and video monitor to the patient’s right positioned inferiorly at the hip and the monitor to the left positioned superiorly at the shoulder (positioning the monitor to the left positioned superiorly at the shoulder (positioning forms a plane parallel to the root of the small bowel mesentery allowing forms a plane parallel to the root of the small bowel mesentery allowing the surgeon to look and work in the same direction as the camera the surgeon to look and work in the same direction as the camera orientation) orientation)

Flexible configuration of the operating room arrangement permits Flexible configuration of the operating room arrangement permits modifications during the operationmodifications during the operation

Patients prepared and draped to allow conversion to an open procedure Patients prepared and draped to allow conversion to an open procedure when necessarywhen necessary

Interventions performed under general endotracheal anesthesia with a Interventions performed under general endotracheal anesthesia with a nasogastric tube and urinary catheter in place. nasogastric tube and urinary catheter in place.

Because nitrous oxide as an anesthetic gas has been found to produce bowel Because nitrous oxide as an anesthetic gas has been found to produce bowel dilatation, its use was specifically avoided in most patients. dilatation, its use was specifically avoided in most patients.

Laparoscopic Management of Small Bowel Obstruction: Indications and Outcome Enrique Luque-de Laparoscopic Management of Small Bowel Obstruction: Indications and Outcome Enrique Luque-de Ledn, MD, Altjandro Metzger, MD, Gregory G Tsotos, MD,Ledn, MD, Altjandro Metzger, MD, Gregory G Tsotos, MD, J GASTROINTEST SURG J GASTROINTEST SURG 1998;2:132-1401998;2:132-140

5mm trocars in the RUQ and LLQ maximize the distance from the trocars

to the iliocecal valve and Ligament of Treitz, respectively.

MONITOR 1

MONITOR 2

Laparoscopic approach to postoperative adhesive obstruction G Borzellino, S Laparoscopic approach to postoperative adhesive obstruction G Borzellino, S Tasselli, G Zerman, C Pedrazzani, G ManzoniTasselli, G Zerman, C Pedrazzani, G Manzoni Surg Endosc Surg Endosc (2004) 18: 686–690(2004) 18: 686–690

Preoperative ultrasonographic mapping of Preoperative ultrasonographic mapping of abdominal wall adhesions has an important abdominal wall adhesions has an important role to play in the selection of patients and for role to play in the selection of patients and for first trocar placement.first trocar placement.

In their experience, this evaluation eliminates In their experience, this evaluation eliminates the risk of visceral injuries and enables the the risk of visceral injuries and enables the best location for successive trocars.best location for successive trocars.

Peritoneal access and Peritoneal access and potential trocar injury to potential trocar injury to distended bowel affect the distended bowel affect the feasibility of laparoscopic feasibility of laparoscopic adhesiolysisadhesiolysis

Initial trocar should be Initial trocar should be placed away from scars placed away from scars (alternative site technique) to (alternative site technique) to avoid adhesions. RUQ or avoid adhesions. RUQ or LUQ placement is also LUQ placement is also acceptable.acceptable.

Midline incision

Initial trocar

X

AccessAccess Alternative site entry can be performed Alternative site entry can be performed

with an open (Hasson) or blind-access with an open (Hasson) or blind-access (Veress needle) technique. The open (Veress needle) technique. The open approach is more prudent in cases of approach is more prudent in cases of laparoscopy for small bowel obstructionlaparoscopy for small bowel obstruction

Careful dissection is required to avoid injury to the underlying Careful dissection is required to avoid injury to the underlying adherent bowel. Blind cutting or spreading must be avoided.adherent bowel. Blind cutting or spreading must be avoided.

The open technique does not eliminate the risk of bowel injury – The open technique does not eliminate the risk of bowel injury – it allows the surgeon to promptly identify and repair any injury it allows the surgeon to promptly identify and repair any injury that may occur.that may occur.

Optical access Optical access trocarstrocars

In experienced hands, optical access In experienced hands, optical access trocars are safe and facilitate rapid trocars are safe and facilitate rapid entry into the peritoneal cavity entry into the peritoneal cavity

A 0-degree laparoscope is inserted through a transparent cannula A 0-degree laparoscope is inserted through a transparent cannula as the trocar is advanced through the abdominal wall enabling as the trocar is advanced through the abdominal wall enabling visualization of consecutive tissue layersvisualization of consecutive tissue layers

This allows identification of the bowel wall before possible trocar This allows identification of the bowel wall before possible trocar puncture occurspuncture occurs

If an injury does occur, it is recognized immediately and If an injury does occur, it is recognized immediately and managed appropriatelymanaged appropriately

ToolsTools Adhesiolysis with scissors Adhesiolysis with scissors

is inconvenient due to bleeding is inconvenient due to bleeding but remains the best method but remains the best method

Electrodissection causes charring of Electrodissection causes charring of tissue and delayed perforations because of excessive heat productiontissue and delayed perforations because of excessive heat production

Bipolar electrosurgery has the advantage of reducing the Bipolar electrosurgery has the advantage of reducing the electrosurgical complications but has delayed thermal lesionselectrosurgical complications but has delayed thermal lesions

The ultrasonically activated scalpel causes less heat production The ultrasonically activated scalpel causes less heat production compared with electrocautery dissection, theoretically lowering the compared with electrocautery dissection, theoretically lowering the risk of delayed perforationsrisk of delayed perforations

Laser is another modality used more by gynecologistsLaser is another modality used more by gynecologists

Aqua dissection and Suction irrigation dissectionAqua dissection and Suction irrigation dissection

VisualizationVisualization Some degree of adhesiolysis is needed along Some degree of adhesiolysis is needed along

the anterior abdominal wall. Techniques the anterior abdominal wall. Techniques include finger dissection through the initial include finger dissection through the initial trocar site and using the camera to bluntly trocar site and using the camera to bluntly dissect the adhesionsdissect the adhesions

Gentle retraction of adhesions may separate the tissue planes – most often Gentle retraction of adhesions may separate the tissue planes – most often sharp adhesiolysis is required. The best technique is to follow the line of sharp adhesiolysis is required. The best technique is to follow the line of tissue adherence, resulting in less bleeding and risk for bowel injury. A tissue adherence, resulting in less bleeding and risk for bowel injury. A traction-countertraction technique as used for open adhesiolysis is effective.traction-countertraction technique as used for open adhesiolysis is effective.

When dense adhesions are present, the plane between bowel and peritoneum When dense adhesions are present, the plane between bowel and peritoneum is often obliterated. It is then necessary to dissect in the preperitoneal fat. is often obliterated. It is then necessary to dissect in the preperitoneal fat.

Usually at least two additional trocars are needed, placed along (not against) Usually at least two additional trocars are needed, placed along (not against) the sights of the camera and added as needed.the sights of the camera and added as needed.

DissectionDissection Sharp dissection with laparoscopic scissors Sharp dissection with laparoscopic scissors

should be used to cut the adhesionsshould be used to cut the adhesions Cautery should be avoided to prevent potential Cautery should be avoided to prevent potential

thermal injury to adjacent bowel. It also causes thermal injury to adjacent bowel. It also causes tissue ischemia (a potent adhesion promoter) tissue ischemia (a potent adhesion promoter) leading to the formation of more leading to the formation of more intraabdominal adhesions.intraabdominal adhesions.

Only pathologic adhesions should be lysedOnly pathologic adhesions should be lysed

Additional adhesiolysis adds to OR time and surgical risks without benefitAdditional adhesiolysis adds to OR time and surgical risks without benefit

If the point of obstruction is not clearly identified adhesiolysis should continue If the point of obstruction is not clearly identified adhesiolysis should continue until all suspicious adhesions or bands are transecteduntil all suspicious adhesions or bands are transected

If all adhesions cannot be lysed conversion to an open procedure must be If all adhesions cannot be lysed conversion to an open procedure must be consideredconsidered

Once adequate adhesiolysis is completed the area lysed should be thoroughly Once adequate adhesiolysis is completed the area lysed should be thoroughly

inspected for possible bleeding, bowel injury, bladder and ureteral injury.inspected for possible bleeding, bowel injury, bladder and ureteral injury.

Small bleeding points may be controlled with clips, sutures, or careful cauterySmall bleeding points may be controlled with clips, sutures, or careful cautery

TechniqueTechnique Using atraumatic laparoscopic forceps, the Using atraumatic laparoscopic forceps, the

surgeon follows the distended loops of bowel surgeon follows the distended loops of bowel to identify the zone of transition from to identify the zone of transition from dilated to collapsed loops. This maneuver dilated to collapsed loops. This maneuver requires patience and both hands.requires patience and both hands.

We recommend beginning the exploration We recommend beginning the exploration

from collapsed bowel loops to prevent incidental bowel injury.from collapsed bowel loops to prevent incidental bowel injury.

The need for enterotomy can be reduced only if meticulous care is taken The need for enterotomy can be reduced only if meticulous care is taken using atraumatic graspers and if the manipulation of friable, distended using atraumatic graspers and if the manipulation of friable, distended bowel is minimized by handling the mesentery whenever possible.bowel is minimized by handling the mesentery whenever possible.

Grasping the mesentery in order to manipulate the bowel decreases the Grasping the mesentery in order to manipulate the bowel decreases the likelihood of direct trauma.likelihood of direct trauma.

Changing the scope port is crucial at times allowing visualization from Changing the scope port is crucial at times allowing visualization from different anglesdifferent angles

Overzealous retraction of thin-walled small bowel fixed intraperitoneally Overzealous retraction of thin-walled small bowel fixed intraperitoneally during manipulation may also lead to iatrogenic enterotomiesduring manipulation may also lead to iatrogenic enterotomies

Technique, Technique, continuedcontinued When “running” bowel between the two When “running” bowel between the two

manipulating bowel clamps, manipulating bowel clamps, both both clamps clamps must remain in view (if a clamp leaves the must remain in view (if a clamp leaves the visual field it is difficult to appreciate the visual field it is difficult to appreciate the amount of traction being applied), also if an amount of traction being applied), also if an enterotomy should occur it may not be appreciated. enterotomy should occur it may not be appreciated.

Repair of an iatrogenic enterotomy may not require conversion to open celiotomy – it Repair of an iatrogenic enterotomy may not require conversion to open celiotomy – it can be accomplished either by intracorporeal suturing’* or extracorporeal repair, can be accomplished either by intracorporeal suturing’* or extracorporeal repair, exteriorizing the involved bowel.exteriorizing the involved bowel.

If an enterotomy occurs during dissection, it should be marked with an endoloop for If an enterotomy occurs during dissection, it should be marked with an endoloop for later addressing.later addressing.

If there is a question whether an enterotomy has occurred: If there is a question whether an enterotomy has occurred: desufflate, then shake the abdomen. Several minutes later reinssufflate and reinspect desufflate, then shake the abdomen. Several minutes later reinssufflate and reinspect the area and check for the presence of bile.the area and check for the presence of bile.

If a bladder injury is suspected check for COIf a bladder injury is suspected check for CO22 distension of the foley bag. distension of the foley bag.

If a ureteral injury is suspected inject methylene blue or perform cystoscopy.If a ureteral injury is suspected inject methylene blue or perform cystoscopy.

ConclusionConclusion

Safe adhesiolysis requires proper surgical meticulous Safe adhesiolysis requires proper surgical meticulous techniques and skills.techniques and skills.

Conversion to a laparotomy should not be considered a Conversion to a laparotomy should not be considered a failure or complication, but rather a recognition of failure or complication, but rather a recognition of limitations posed by technology, the surgical expertise, limitations posed by technology, the surgical expertise, or factors unique to a particular patient or disease or factors unique to a particular patient or disease process. process.