Prevalence of anatomical variants and coronary anomalies in 543 consecutive patients studied with 64-slice CT coronary angiography

The aim of our study was to assess the prevalence of variants and anomalies of the coronary artery tree in patients who underwent 64-slice computed tomography coronary angiography (CT-CA) for suspected or known coronary artery disease. A total of 543 patients (389 male, mean age 60.5 ± 10.9) were reviewed for coronary artery variants and anomalies including post-processing tools. The majority of segments were identified according to the American Heart Association scheme. The coronary dominance pattern results were: right, 86.6%; left, 9.2%; balanced, 4.2%. The left main coronary artery had a mean length of 112 ± 55 mm. The intermediate branch was present in the 21.9%. A variable number of diagonals (one, 25%; two, 49.7%; more than two, 24%; none, 1.3%) and marginals (one, 35.2%; two, 46.2%; more than two, 18%; none, 0.6%) was visualized. Furthermore, CT-CA may visualize smaller branches such as the conus branch artery (98%), the sinus node artery (91.6%), and the septal branches (93%). Single or associated coronary anomalies occurred in 18.4% of the patients, with the following distribution: 43 anomalies of origin and course, 68 intrinsic anomalies (59 myocardial bridging, nine aneurisms), three fistulas. In conclusion, 64-slice CT-CA provides optimal visualization of the variable and complex anatomy of coronary arteries because of the improved isotropic spatial resolution and flexible post-processing tool.
Introduction
Since the beginning of the 1990s, a variety of non-invasive techniques have been introduced in coronary artery imaging in an attempt to replace invasive conventional coronary angiography (CCA). These techniques have shown promising results, although they were considered inadequate for large-scale clinical implementation. Furthermore, advanced modalities such as magnetic resonance (MR) and electron-beam computed tomography (EBCT) are still not widely available on the territory [1–6]. The introduction of multislice computed tomography coronary angiography (MSCT-CA) allowed the detection of significant coronary artery stenosis. Improved performance of 64-slice CT equipment, characterized by isotropic spatial resolution and faster temporal resolution, provided a valid alternative to CCA in selected patient populations [7–11].
MSCT-CA is currently considered the ideal tool to three-dimensionally visualize the complex and tortuous anatomy of coronary arteries [12, 13]. Previous studies with four- and 16-slice CT-CA demonstrated that anomalous coronary arteries may be defined [14–16]. However, to the best of our knowledge, 64-slice studies with large patient series have not yet been published. In the present study, a large patient population who underwent 64-slice CT-CA was reviewed to assess the prevalence of coronary artery variants and anomalies.
Materials and methods
Population
A total of 543 consecutive patients (389 male, 154 female, mean age 60.5 ± 10.9, range 21–87 years), who underwent 64-slice CT-CA from 27/07/2004 to 28/02/2006 in our department, were reviewed for coronary artery variants and anomalies. The majority of patients (n = 476) were scheduled for CCA because of suspected or known coronary artery disease (CAD). The other 67 patients were addressed to 64-slice MSCT-CA after CCA to determine the three-dimensional image of a suspected origin or course anomaly. The indication for MSCT-CA were: atypical angina (n = 111), typical angina with inconclusive stress test (n = 162), presence of risk factors and high risk of major coronary events (n = 46), proximal stent patency follow-up (n = 112) and by-pass patency follow-up (n = 45). The Institutional Review Board approved the study protocol.
CT scan and reconstruction parameters
All examinations were performed with a 64-slice CT scanner (Sensation 64, Siemens, Forcheim, Germany) with the following parameters: slices/collimation 32/0.6 mm, rotation time 330 ms, effective temporal resolution (with 180° algorithm) 165 ms, 120 kv, 900 mAs, table feed/s 11.63 mm, effective slice thickness 0.6 mm, reconstruction increment 0.3 mm, field of view (FOV) 140–180 mm, isotropic voxel resolution of 0.4 × 0.4 × 0.4 mm.
Patients with heart rate >70 bpm received 100 mg of metoprolol per os 1 h prior the examination. A bolus of 100 ml of high iodinated contrast material (400 mg/ml iomeprol, Iomeron 400, Bracco, Milan, Italy) was injected into an antecubital vein of the right arm with a flow rate of 5 ml/s, followed by a 40-ml saline chaser. A bolus-tracking technique was used for the synchronization between arterial passage of contrast material and MSCT-CA.
Data were reconstructed by retrospective gating in end-diastolic phase (from -300 to -450 ms before the peak of the subsequent R wave) or end-sistolic phase to better image the right coronary artery (RCA).
Image and data analysis
All CT examinations were reviewed by three radiologists (L.L.G., R.M. and F.A.) with a level 3 expertise in cardiac CT [17], who loaded the datasets off-line into a dedicated workstation (Leonardo, Siemens, Germany). A total number of 559 examinations were performed and only 13 scans were considered not assessable by the readers in consensus due to poor image quality (severe breathing, triggering or motion artefacts).
All data were analysed with post-processing tools such as multiplanar reconstructions (MPR), curved MPR (cMPR), maximum intensity projections (MIP), and volume rendering (VR) to three-dimensionally image the complex anatomy of the coronary artery tree. Disagreement was solved by a consensus reading. Segments were classified according to the American Heart Association (AHA) scheme. Variants considered were: the coronary dominance (right, left, balanced), the variable origin of the conus branch and sinus node artery, the left main (LM) length, the presence of the intermediate branch, the number of diagonal and marginal branches. Anomalies of origin and course, intrinsic coronary anomalies (myocardial bridging, aneurisms >1.5 mm) and termination anomalies (fistulas) were checked. Prevalence data of single coronary artery variants and anomalies were collected.
Results
Our cohort results were heterogeneous because of the multi-ethnic Dutch population (immigrants 11%, Table 1).
Table 1Our population resulted heterogeneous because of the multiethnic Dutch populationEthnic group% (n)The Netherlands88.95 (483)Middle East Asia3.31 (18)South-East Asia2.94 (16)East Europe1.84 (10)South Europe1.10 (6)South America0.92 (5)Africa0.92 (5)
Most of coronary segments were identified, although with a variable rate due to different diameters (Table 2). The anatomical variants of the coronary artery tree are extremely frequent (Table 3). According to the literature, the dominance was right in 86.6% (n = 470), left in 9.2% (n = 50), balanced in 4.2% (n = 23) [18]. The LM trunk (segment 5) presented a variable length (mean 112 ± 55 mm, range 17–601 mm, median 106 mm): <1 cm (n = 226, 41.6%), 1–2 cm (n = 257, 47.3%), and >2 cm (n = 38, 7%) (Fig. 1). The LM trunk was absent in 22 cases (4.1%) due to split origin of the left coronary artery (LCA) (n = 18, 3.3%) or other origin anomalies (n = 4, 0.7%). A variable number of diagonal branches was observed: one diagonal branch in 136 cases (25%), two diagonal branches in 270 cases (49.7%), and more than two in 130 cases (24%) (Fig. 2). No diagonal branches were visualized in just seven cases (1.3%). Marginal branches of the left circumflex (LCX) artery were observed in the 99.4% (n = 540): one in 191 cases (35.2%), two in 251 cases (46.2%), and more than two in 98 cases (18%) (Fig. 2).
Table 2Segments visualized according to the American Heart Association classificationSegments% (n)199.8 (542)299.3 (539)397.8 (531)492.4 (502)595.9 (521)6100 (543)7100 (543)897.8 (531)998.7 (536)1073.7 (400)11100 (543)1299.4 (540)1397.2 (528)1464.3 (349)1572.4 (393)16a21.9 (119)aSegment 16 refers to the intermediate branchTable 3Prevalence of coronary artery variants (RCA right coronary artery, LAD left anterior descending artery, LCX left circumflex, LM left main, ND not detected)Variants Patients % (n)Conus branchFrom proximal RCA64.1 (348)From ostial RCA22.3 (121)From aorta11.6 (63)ND2 (11)Sinus node arteryFrom RCA65.4 (355)From LCX16.6 (90)From RCA and LCX9.2 (50)From LCX and pulmonary artery0.2 (1)From aorta0.2 (1)ND8.4 (46)LM length<1 cm41.6 (226)1–2 cm47.3 (257)>2 cm7 (38)Intermediate branch21.9 (119)Diagonal branches from LADND1.3 (7)125 (136)249.7 (270)>224 (130)Septal branches from LAD93 (505)Marginal branches from LCXND0.6 (3)135.2 (191)246.2 (251)>218 (98)Fig. 1a LM length. b The separate origin of the LAD and LCX might cause technical difficulties during coronary angioplasty due to poor visualization. c–e The LM may present variable lengthFig. 2Variable number and course of diagonal (a–c) and marginal branches (d–f).The intermediate branch courses along the anterior wall of the left ventricle with a variable pattern (g–i)
When the intermediate branch supplies the vascularization of the antero-lateral wall of the left ventricle, a decreased number of diagonal branches (segments 9 and 10) was observed: one, 38.6%; two, 43.7%; more than two, 14.3%; none, 3.4% (Fig. 2).
Furthermore, CT-CA may visualize smaller branches, such as the conus branch artery (532/543, 98%), the sinus node artery (497/543, 91.6%), and the septal branches (505/543, 93%). The conus branch artery may arise from the right coronary artery (RCA) (64.1%), in proximity with the RCA ostium (22.3%) or from the aorta (11.6%). The sinus node artery may originate from the RCA (355/543, 65.4%), from LCX (90/543, 16.6%), from RCA and LCX (50/543, 9.2%), from LCX and pulmonary artery (0.2%), or from aorta (0.2%) (Fig. 3).
Fig. 3The variable origin of the conus branch artery (arrow): from RCA (a), in proximity with the ostium (b), and from aorta (c). The variable origin of the sinus node artery (arrowhead): from RCA (d), from LCX (e), or both pathways may be present (f)
Coronary anomalies were observed in the 18.4% of our population (n = 100). Patients presented single or associated coronary anomalies (Table 4).
Table 4Prevalence of coronary artery anomalies (LM left main artery, PDA posterior descending artery)Coronary anomaliesPatients % (n)Myocardial bridging10.9 (59)Absent LM3.3 (18)Rotation of the aortic root with normal coronary origin from the sinuses of Valsalva2.6 (14)Coronary aneurysms1.6 (9)Anomalies of origin and course1.5 (8)Fistulas0.5 (3)Early take-off of PDA0.5 (3)
Single or multiple myocardial bridging was visualized in 59 patients (10.9%) (Fig. 4). Forty-three anomalies of origin and course were found with the following distribution: absence of left main artery occurred in 18 patients (3.3%), origin anomalies of the RCA and the LCA caused by rotation of the aortic root between 45° and 90° (with normal coronary origin from the sinuses of Valsalva) in 14 patients (2.6%), anomalies of origin and course (with anomalous origin from the sinuses of Valsalva) in eight patients (1.5%), early take-off of the posterior descending artery in three patients (0.5%). The anomalies of origin and course encountered were: three retroaortic LCX (two arising from RCA, one from the right sinus of Valsalva), two inter-arterial LCAs from RCA, two inter-arterial RCAs from the left sinus of Valsalva, one septal RCA from left sinus of Valsalva (Fig. 5).
Fig. 4Examples of myocardial bridging (arrowhead). Myocardial bridging of mid-LAD displayed by MPR (a) and VR (b) images. Another case of myocardial bridging depicted by conventional angiogram in systole (c), not visualized in diastolic image (d), and clearly displayed by VR image (e)Fig. 5Anomalies of origin and course (arrowhead). VR (a) and MIP (b) images of a LCA arising from the RCA with a septal course as confirmed by conventional angiogram (c). VR (d) and MIP (e) images of a RCA arising from the left sinus of Valsalva with an interarterial course, and corresponding conventional angiogram (f). VR (g) and cMPR (h) images of a stented retroaortic LCX arising from the right sinus of Valsalva and corresponding conventional angiogram (i)
Coronary aneurisms (>1.5 mm, if compared with the normal vessel diameter) were identified in nine patients (1.6%) (Fig. 6). Coronary fistulas were observed in three patients (0.5%) (Fig. 7).
Fig. 6Examples of coronary aneurisms. Aneurisms of LCX and LAD displayed by VR (a) and MIP (b) images, and corresponding conventional angiogram (c). Aneurisms of the RCA depicted by VR image (d) and vessel tree isolation (e), confirmed by the conventional angiogram (f)Fig. 7Abnormal termination of coronary arteries. Fistula between the RCA and the coronary sinus depicted by VR (a), coronary tree isolation (b), and MPR images (c). Fistula between the LAD and the right ventricle displayed by VR (d) and coronary tree isolation images (e), and corresponding conventional angiogram (f)
Discussion
The wrong interpretation of a coronary variant or anomaly might cause technical difficulties during interventional procedures or lead to clinical misdiagnosis or major complications might occur during graft surgery. The need for an accurate anatomical evaluation of the coronary artery tree is relevant during angioplasty, due to revascularization purposes [19]. Coronary anomalies are often asymptomatic and may be accidentally discovered. Given the increase of interventional procedures, the detection of coronary anomalies is becoming of major clinical importance [20]. The coronary anomalies cannot be considered just rare aspects because they may often lead to relevant clinical consequences [21].
In an attempt to clarify the variability of the coronary artery tree, Angelini et al. [18] proposed these definitions: normal, any morphological feature observed in >1% of an unselected population; normal variant, an alternative, relatively unusual, morphological feature seen in >1% of the population; and anomaly, a morphological feature (number of ostia, proximal course, termination) rarely encountered (<1%) in the general population. However, the incidence of coronary anomalies is relevant not only for conceptual and educational purposes but, more importantly, for public health issues, given that 5.6% of the total American population could have some kind of coronary anomaly [18]. Moreover, the 19% of sudden deaths in young athletes are related to these anomalies [22]. That is a reason why the diagnosis of coronary anomalies should be a healthcare priority.
To date, despite some limitations, CCA has been the “gold standard” for the diagnosis of coronary anomalies. Selective catheterization and subsequent interpretation of vessel anatomy may be difficult in CCA because the operator is not aware of an atypical location of the vessel orifice. Therefore, the diagnosis of a coronary anomaly is often established on the impossibility of finding the coronary arteries in their normal anatomical position. Finally, interpretation of the courses of anomalous coronary arteries may be erroneous because CCA is two-dimensional and cannot provide enough information about the complex three-dimensional vessel anatomy [18, 23, 24]. The study with the largest number of cases, performed in North America at the Cleveland Clinic on 126,595 patients who underwent coronary angiography, reported a 1.3% incidence [25]. In recent years, other techniques in cardiologic diagnostic imaging have been developed, such as trans-thoracic echocardiography (TTE), trans-oesophageal echocardiography (TEE), magnetic resonance angiography (MRA), EBCT and MSCT [1–4].
TTE, which is used mainly in paediatric radiology, does not always provide reliable diagnostic results. When performed on adult patients, it proves difficult to obtain diagnostic images owing to the interposition of the bones of the ribcage (ribs and sternum), pulmonary parenchyma and subcutaneous adipose tissue [5, 26].
Data reported in the literature suggest that TEE is more sensitive than TTE in identifying coronary anomalies and assessing their course, although it remains an invasive technique (i.e. insertion of a probe down the oesophagus and a varying degree of sedation according to patient tolerance required to perform the examination) characterised by a significant level of operator dependence and therefore impossible to perform as a screening test [6]. In addition, both echocardiography techniques are able to assess only the proximal tract of the coronary arteries, and therefore, their diagnostic capabilities are limited to only a part of coronary arteries [6].
MRA is a highly promising technique since no ionising radiation is used. In the study of the origin of the coronary arteries, MRA can provide more complete information than CCA, particularly in patients with other concomitant congenital cardiac anomalies [1, 27]. The main limitation of MRA is incomplete visualisation of the coronary vessels, particularly their distal tracts. This limits the diagnostic capabilities for the assessment of fistulas, the origin of coronary arteries other than the aortic sinuses (i.e. from the pulmonary artery) and collateral vessels. However, MRA provides optimal functional assessment of complex congenital heart disease including anomalies of great vessels, and cardiac chambers and valves (the procedures may include evaluation of ventricular mass and volumes, quantification of valvular disease, and contrast enhancement) [12].
Ropers et al. [2] firstly studied the ability of contrast-enhanced EBCT to identify anomalous coronary arteries and their course with good accuracy. Recent advances in MSCT-CA equipments have continuously improved the quality of non-invasive coronary artery imaging. Various studies have demonstrated a high accuracy of coronary angiography with MSCT-CA for the diagnosis of CAD. In particular, the high negative predictive value of 64-slice CT allows to reliably exclude significant coronary artery stenoses [7–11]. Given the high sensitivity and negative predictive value of the technique, MSCT could represent a non-invasive alternative to CCA in patients prior to cardiac valve surgery. By selecting only those patients with coronary significant lesions to undergo CCA, MSCT-CA could avoid cardiac catheterization in a large number of patients without CAD [28]. The latest advance of CT technology is represented by the dual-source CT coronary angiography (DSCT-CA), with improved temporal resolution of 83 ms. Scheffel et al. [29] firstly demonstrated that DSCT-CA provides high diagnostic accuracy for assessment of CAD in a high pre-test probability population with extensive coronary calcifications and without heart rate control.
The advantages of MSCT lie primarily in its high level of diagnostic and anatomical accuracy. The technique offers excellent spatial resolution with the possibility of performing a flexible post-processing (i.e. MPR, MIP, and VR). Previous studies with four- and 16-slice CT-CA confirmed that the complex and tortuous coronary anatomy can be readily visualized and anomalous coronary arteries may be defined [14–16]. To the best of our knowledge, that is the first 64-slice CT-CA with large patient population, which evaluates the prevalence of coronary arteries variants and anomalies.
The AHA classification is the currently used scheme to identify the coronary artery segments and refers to 16 segments, in the attempt to standardize the remarks [30]. Another classification was reported by the BARI group, with emphasis to the coronary dominance pattern [31–33].
According to literature data, the dominance was right in 86.6% (n = 470), left in 9.2% (n = 50) and balanced in 4.2% (n = 23) [18]. The majority of coronary segments was identified according to the American Heart Association scheme.
The intermediate branch was present in 119 patients (21.9%), slightly less than reported in the literature [34]. However, the need for reporting the intermediate branch is stressed by the correlation between its presence and the decreased number of diagonal branches observed.
Furthermore, the septal branches of the left anterior descending artery (LAD) were detected in the 93% (505/543). The opportunity of reporting septal branches of LAD must be taken into account because of the hemodinamic relevance of these vessels.
The prevalence of coronary anomalies was estimated at the 18% (100/543) in our population. This prevalence rate is higher than reported in the literature. However, our department is a major centre for cardiovascular pathologies and many patients were enrolled in non-invasive cardiovascular research projects. Myocardial bridging occurred in the 10.9%, a prevalence more comparable with autopsy rates, than with angiographic series [35]. The split of LCA also had a prevalence higher than reported in the literature [18]. Eighty-five patients with not significant CAD presented 14 coronary anomalies (16.5%). Four hundred and fifty-eight patients with significant CAD (with >50% stenosis, during stent or by-pass follow-up) presented 86 coronary anomalies (18.8%). Therefore, the prevalence was similar in the two groups. However, a bias is given by the fact that 67 patients were addressed to 64-slice CT-CA after CCA to determine the three-dimensional imaging of a suspected anomaly. After excluding these 67 patients, the prevalence of coronary anomalies was higher in the CAD patients (11.4% vs 4.2%). The prevalence of myocardial bridging resulted higher in the CAD group (7.4% vs 2.8%).
There are several limitations in our study. The first one is inherent to the heterogeneous population consisting of various ethnic groups (immigrants 11%) with a substantial age range (21–87 years). The age may affect the development of the collateral vascularization and influence the percentage of segments visualized. A second limitation is related to the high prevalence of origin anomalies, due to the fact that 67 patients were addressed to 64-slice CT-CA after CCA to determine the three-dimensional imaging of a suspected anomaly. As opposed to MRA, which also permits the non-invasive evaluation of coronary anomalies (proximal tracts), MSCT-CA requires radiation and a contrast agent. However, the high spatial and temporal resolution make it reasonable to use MSCT-CA as one of the first-choice imaging modalities in the work-up of known and suspected coronary anomalies [12, 13]. The high radiation exposure should be a matter of concern and debate in young patients. In these patients, the first-choice imaging modality could be MRA. In the case of suspected complex congenital heart disease (including anomalies of great vessels, and cardiac chambers and valves), the use of MRA would be highly advisable, since the optimal evaluation of ventricular and valvular function is provided [12, 13].
Compared with 16-slice CT-CA, 64-slice CT-CA provides improved temporal resolution and isotropic spatial resolution which allow optimal three-dimensional visualization of the variable and complex anatomy of coronary arteries. Sixty-four-slice CT-CA may non-invasively define normal anatomical variants from potentially dangerous anomalies and support the clinical management of referring cardiologists and cardiac surgeons.

anatomical variants
anomalies
multislice computed tomography
coronary artery circulation


Treatment of the neurogenic bladder in spina bifida

Renal damage and renal failure are among the most severe complications of spina bifida. Over the past decades, a comprehensive treatment strategy has been applied that results in minimal renal scaring. In addition, the majority of patients can be dry for urine by the time they go to primary school. To obtain such results, it is mandatory to treat detrusor overactivity from birth onward, as upper urinary tract changes predominantly start in the first months of life. This means that new patients with spina bifida should be treated from birth by clean intermittent catheterization and pharmacological suppression of detrusor overactivity. Urinary tract infections, when present, need aggressive treatment, and in many patients, permanent prophylaxis is indicated. Later in life, therapy can be tailored to urodynamic findings. Children with paralyzed pelvic floor and hence urinary incontinence are routinely offered surgery around the age of 5 years to become dry. Rectus abdominis sling suspension of the bladder neck is the first-choice procedure, with good to excellent results in both male and female patients. In children with detrusor hyperactivity, detrusorectomy can be performed as an alternative for ileocystoplasty provided there is adequate bladder capacity. Wheelchair-bound patients can manage their bladder more easily with a continent catheterizable stoma on top of the bladder. This stoma provides them extra privacy and diminishes parental burden. Bowel management is done by retrograde or antegrade enema therapy. Concerning sexuality, special attention is needed to address expectations of adolescent patients. Sensibility of the glans penis can be restored by surgery in the majority of patients.
Introduction
The incidence of spina bifida worldwide still ranges from 0.3–4.5 per 1,000 births. Renal scarring and renal failure have been important issues in spina bifida literature over the years, with reported death due to renal failure up to 20% in the first year of life. The incidence of renal damage is nearly 100% in patients with an overactive pelvic floor (detrusor/sphincter dyssynergia; DSD) when not adequately treated. It is important to realize that renal damage starts early in life, within the first 6 months. In contrast to a few decades ago, we can now assure parents of children with a neurogenic bladder that renal function can be preserved provided they comply with the treatment regime [1–14].
To prevent renal damage, urological and nephrological treatment of a neurogenic bladder should start immediately after birth. Modern treatment provides the opportunity to convert a high-pressure bladder with functional urethral obstruction based on neuropathic detrusor/sphincter dyssynergia into a low-pressure reservoir that is safe for the upper urinary tracts [15, 16]. The objectives in the urological management of patients with spina bifida are (1) preservation of renal function; (2) quality of life, preferably with urinary dryness by school age; and (3) independence at an older age with respect to bladder and bowel management. Finally, sexuality in the spina bifida patients is an underestimated problem.
Initial approach for the management of spina bifida
To preserve renal function, low bladder pressure must be maintained from birth. The status of pelvic floor activity must be assessed shortly after birth to ascertain whether a child is at risk for high detrusor pressures. At first presentation after birth, inspection of the anal sphincter, closed or open, gives an impression of the status of the pelvic floor: overactive or paralyzed. Approximately 50% of children with spina bifida aperta and 25% of children with occult spinal dysraphism have a detrusor/sphincter dyssynergia that carries a serious risk of early upper urinary tract damage by high bladder pressures and urinary tract infections (UTIs). It is important to realize that after closure of the back, pelvic floor behavior can change from paralyzed to overactive in the first 2–3 months of life. That is a reason to delay the first urodynamic study (UDS) until 2 months after birth.
Clean intermittent catheterization
In principle, all newborn patients are put on clean intermittent catheterization (CIC), oxybutynin, and chemoprophylaxis (trimethoprim 2 mg/kg once daily) immediately after closure of the back. By doing so, safe pressures in the lower urinary tract can be obtained in most patients. In most patients, bladder volume and compliance remain satisfactory for years. In patients with DSD, this approach has also reduced the need for bowel augmentation of the bladder from 90% to less than 5%. Of course, it is still a matter of discussion whether it is necessary to perform CIC from birth onward in all patients. In patients with proven pelvic floor paralysis, it is also possible to wait until after surgery to make the patient continent. However, it can be a tedious affair to teach CIC to an 8-year-old. Parents of these children are advised to catheterize at least twice daily to maintain the habit of CIC. CIC was introduced for neurogenic bladders in 1972 [17–20]. Parents and other caregivers carry out CIC in the first 8–9 years of life: if the children show sufficient dexterity, they take up this task themselves after this age. After birth, CIC is carried out with self-lubricating 8-F catheters. The size of the catheter depends on the patient’s age; the aim is always to use the largest possible catheter to obtain optimal bladder emptying.
Antimuscarinic therapy
Oxybutynin is best started together with CIC immediately after closure of the back. Other antimuscarinic agents have not yet been registered for pediatric use. This subject is more elaborately described in the section “Overactive detrusor”.
Infection prophylaxis
In principle, all patients are put on low-dose chemoprophylaxis, mostly trimethoprim 2 mg/kg per day. In case of breakthrough infections, nitrofurantoin or ciprofloxacin can be used. Symptomatic infections are treated intravenously with amoxicillin/clavulanic acid and gentamicin until the result of bacterial culture is known. Many centres stop prophylaxis after the age of 1 year, and approximately 50% of patients seem to do well without prophylaxis. Scientific proof is lacking on this subject. To obtain such proof, we are doing a multicenter randomized study with half of the patients on prophylaxis and half without.
Specific needs
Overactive pelvic floor
From birth, patients with an overactive pelvic floor generally become dry with the help of oxybutynin and CIC. Every year, UDS are carried out to check bladder activity, capacity, and compliance. Patients are given ultrasound scans for upper-tract dilatation and renal growth. A wait-and-see policy is adopted when bladder capacity is normal for age and end-filling detrusor pressures are 30 cms H2O or less. When bladder compliance is insufficient, with end-filling pressures of more than 30 cms, an autoaugmentation or detrusorectomy can reduce the pressure. Augmentation by ileocystoplasty or colocystoplasty is inevitable in patients with serious overactivity in combination with poor bladder compliance and low capacity. Both operations can be performed at any age and can be combined with other procedures to obtain better urinary continence to facilitate CIC and/or to reduce UTIs (reflux) [21].
Paralyzed pelvic floor
Patients with a paralyzed pelvic floor are incontinent for urine. Their upper urinary tracts are safe as long as the paralytic pelvic floor is left untreated. They need bladder-neck surgery to become dry. If bladder capacity and compliance are insufficient, surgery can be combined with autoaugmentation of the bladder (detrusorectomy) or (rarely) with clam ileocystoplasty or colocystoplasty.
Overactive detrusor muscle
If UDS reveals detrusor overactivity, patients are treated with antimuscarinics to increase bladder capacity, even if detrusor pressures are safe. Life-long suppression of detrusor overactivity is required in patients with an overactive neuropathic bladder. In some patients, overactivity can be treated surgically by detrusorectomy or ileocystoplasty. In spina bifida, rhizotomies (interruption of spinal roots) are not yet being used routinely to cure overactivity, but they seem to be a promising alternative. Ideally, we would like to start a protocol with neonatal rhizotomies during the first back closure, but so far, practical and ethical considerations have prevented us from doing this. Antimuscarinic therapy is the gold standard for pharmaceutical therapy of neuropathic detrusor overactivity. Oxybutynin has proven to be inexpensive and effective and can be taken orally, intravesically, and transdermally. Several new antimuscarinic agents have been introduced, which may prove valuable in the future.
Repeated injection therapy of the bladder with 300 U of botulinum toxin can be an alternative to antimuscarinic therapy. This therapy effectively suppresses detrusor contractions for 6–9 months. Injections need to be repeated at a 6- to 9-month interval. Adverse effects, even after repeated injection therapy, have not been reported. The long-term effects have yet to be established [22, 23].
Surgical procedures
Timing of surgery
There is no age-related contraindication for any operation. Thus, indication for surgery is made in mutual agreement with the child’s parents or with the patients themselves after the age of 11 years. The combination of high bladder pressures and vesicoureteral reflux can sometimes force intervention as early as the first few months of life. We combined antireflux surgery, bladder autoaugmentation, and transvaginal sling suspension in a 3-month-old girl with febrile breakthrough infections, with good clinical and urodynamic result after follow-up for more than 10 years. Initially, reserves existed on doing sling suspensions before puberty, especially in boys, out of fear of introducing obstruction during puberty based on prostate growth. Over the years, it has been proven that puberty can safely be passed after sling suspension of the bladder neck, both in girls and boys.
Parental burden can be an indication for performing a catheterizable stoma. If a child weighs 20 kg, five daily transfers for CIC can be too much for a parent with lower back pain. Finally, the patient’s privacy can be an important argumentation for construction of a stoma for CIC. Parents are increasingly reluctant for any caregiver to help their child perform CIC transurethrally, as this involves exposure of the genitalia to strangers several times a day.
Surgery for incontinence
Patients with a paralytic pelvic floor need bladder-neck surgery to achieve continence. There are many surgical options. Our standard approach is an abdominoperineal puboprostatic sling procedure in boys and a transvaginal sling procedure in girls. If there is some persistent leaking after a sling procedure, this is cured by injecting a bulking agent in the bladder neck. Optimal results are obtained if the injection needle is passed into the bladder neck by means of a suprapubic puncture with transurethral endoscopic visual control. So far, we have mainly used silicon grains in povidone (Macroplastique®) as a bulking agent. The polymer Deflux® offers a good alternative because it is easier to inject. However, in our experience, Deflux does not work if CIC needs to be carried out through the same channel. A recent survey, yet unpublished, of the results of 76 sling suspensions revealed an 80% success rate.
Sling suspension in boys
There is a great variety in the reported results regarding sling suspension of the bladder neck in boys with neuropathic sphincter incompetence, especially when compared with girls. The plane between the bladder neck/prostate and the rectum must be developed to allow the sling to be wrapped around the bladder neck. There are three possible techniques, each with their specific advantages and disadvantages. First, from the abdominal wound, the pelvic diaphragm can be opened left and right so that a pathway can be bluntly dissected for the sling around the bladder neck. A disadvantage of this technique is the risk of passing into the prostatic urethra with the right angle that is used to feel the way around during surgery. Experienced urologic surgeons do not take this argument seriously, but in practice, most surgeons perform this operation with the relatively low frequency of only a few cases a year. The second possible technique is the abdominoperineal approach to develop the plane between the bladder neck and the urethra. The plane between the rectum and the bladder neck is exposed through a perineal incision. The most important advantages of this procedure are the short time, approximately 20 min, needed to develop the plane around the bladder neck and the fact that the bladder does not need to be touched at all [24].
A third method to find the path around the bladder neck has been proposed by Lottmann et al. The complete bladder is dissected from the peritoneum and the rectum until only the urethra and both ureters with the vascular pedicles are left. The sling can easily be passed around the bladder neck, with direct visual control and exactly at the level of the bladder neck [25]. It is difficult to determine which of these three approaches is the best. All three have enthusiastic followers. At our department, we have had two urethral defects treated by two experienced surgeons in a small series of the abdominal approach going directly around the bladder neck. We have had one urethral defect leading to bladder-neck closure in 76 patients operated on abdominoperineally. Our experience with the Lottmann approach is limited to three successful cases and, because of operation time and for fear of limited bladder vascularization, we abandoned this approach.
Another important subject is the amount of tension that needs to be put on the sling. In the past, we tried to regulate tension by measuring urethral and leak-point pressures during surgery, but there was no significant positive outcome. Nowadays, we determine sling tension by measuring the ability to pass a relatively large Foley catheter past the sling; for example, a 12-F catheter in a 7-year-old boy. In some patients with anal atresia after prior rectal pull-through surgery, it may be necessary to adopt the abdominal approach to pass around the bladder neck. Abdominoperineal operations in 14 patients, published in 1999, led to continence in all 14 patients; one patient required a subsequent injection of a bulking agent to help achieve continence [24]. It is important to note that in this series, the erectile function of the penis proved to be preserved after sling suspension.
False routes are a risk after sling suspension. Out of approximately 50 male patients, we had to construct a catheterizable stoma in five: four as a result of a false route, and one because of a huge congenital prostatic cyst.
Sling suspension in girls
In general, sling suspension of the bladder neck in girls leads to good results concerning urinary continence. There are also several ways to find the way around the bladder neck in girls. The standard well-known technique is to identify the level of the bladder neck by feeling the balloon of a transurethral Foley catheter, and, subsequently, developing the plane between the bladder neck and the anterior vaginal wall from above. This procedure can be very difficult in girls with severe spine deformities. There is always a certain risk of entering the urethra or the bladder neck when passing around. This is also the case in patients with a normal anatomy. To avoid this risk, in postpuberty female patients, many surgeons opt for incising the vaginal wall at the level of the bladder neck and bringing the sling around under direct visual control. We chose to put the sling through the vagina, first only in prepubertal girls and later in all patients. This method has two major advantages: there is no risk of bladder-neck lesions and only a small risk of sling erosion [26]. In spina bifida patients, the risk of sling erosion is higher than in patients with stress incontinence, because the sling must be tightened more strongly in patients with neuropathic sphincter incompetence.
Alternatives
There are many surgical alternatives for reaching urinary continence. Kropp and Pippi Sale developed operations to create a flap valve from the bladder neck. Young/Deese/Leadbetter, Tanagho, and Mitchell procedures lengthen the urethra into the bladder. Several authors prefer American Medical Systems (AMS) artificial sphincters to help reach continence. The majority of patients still need CIC after AMS sphincter prosthesis [27]. We found that Burch-type colposuspension was insufficient for spina bifida girls to reach urinary continence. This is related to the huge intra-abdominal pressure that can result from transfers from the wheelchair.
Several groups do not opt for urinary continence at an early age and try to maintain safe leak-point pressures by regular dilatation of the female urethra, sometimes also of the male urethra, after making this possible with a perineal urethral stoma. In some patients, they construct a cutaneous vesicostomy for the first few years and perform an ileocystoplasty when the stoma is closed.
Alternatives in dealing with a neurogenic bladder
When cerebral function is bad and the patient has no dexterity, diapers can also be chosen. For this choice, a low-pressure bladder is necessary. Good results are obtained by cutaneous vesicostomy. In girls, low pressures can be achieved by making a vesicovaginal fistula by endoscopic cutting into the vagina between the ureteric orifices. Temporary low pressures can be achieved by overdistension of the female urethra. In boys, endoscopic external sphincterotomy in the 12 o’clock position produces low outlet resistance for 2–3 years and needs to be repeated when bladder pressures rise.
Catheterizable stomas
The need for transfers from a wheelchair to do CIC is the most important indication to make a catheterizable stoma. Sometimes in boys, the impossibility of carrying out CIC transurethrally after false routes results in the need for a stoma. Parents increasingly indicate their child’s privacy as a reason for asking for a catheterizable stoma. In patients with a large bladder capacity for their age, a continent stoma can be constructed from a bladder tube. Patients with a normal bladder capacity can be treated by cutaneous appendicovesicostomy or by an ileal tube (Monti procedure) [28]. The direction of peristalsis from the appendix (Fig. 1) needs to go in the direction of the bladder to avoid mucus spotting in the clothes. When ileal or colonic bladder augmentation is performed at the same time, the continent stoma can be constructed from the side or middle part of the gut used for the augmentation. In some patients, a ureter can be used as a catheterizable stoma. The intravesical tunnel of the tube in the bladder should be at least 2 cm long, as there is a risk that the tunnel will end up being too short, especially in case of an extravesical implantation of an appendix.
Fig. 1The appendix can be used to make a stoma to the bladder for intermittent catheterization
In the literature, after construction of a catheterizable stoma, complications are described in as many as 50% of patients. These complications are mostly temporary. Stomal stenosis, mostly at skin level, is a frequently occurring temporary complication that can be avoided with a silicon ace stopper left behind in the skin portion of the stoma for 6 months between catheterizations. Stomal leakage of urine can be a frustrating complication. Endoscopic treatment with bulking agents can be tried, but lengthening of the intravesical tunnel or reimplantation of the stoma will often be needed. Leakage of the stoma occurs more often in midline stomas (umbilicus) than in stomas placed on the right side of the lower abdominal wall. The reason is probably that the lateral stoma passes through the rectus muscle and is thus occluded during increases in abdominal pressure due to rectus contraction. In midline stomas we now also pass the stoma through the median margin of one rectus muscle. Stoma stenosis at the level of entrance into the bladder can sometimes be treated endoscopically with success. In those patients, formal reimplantation of the stoma into the bladder will frequently be needed as well.
Autoaugmentation or detrusorectomy of the bladder
In general, not too much extra capacity should be expected, but high-end filling pressures based on low bladder compliance can be reduced to safe values by detrusorectomy. In selected patients that undergo surgery to become dry, we also do an autoaugmentation (Fig. 2) to try and get patients off antimuscarinic therapy, with success in approximately 50% of cases. An important factor for success is identification, opening, and marking the adventitial layers of the bladder separately before the detrusorectomy starts, and the meticulous closure of this layer at the end of the procedure. This means that before the start of the detrusorectomy, the detrusor has been freed of all adventitial layers. If a mucosal leak occurs during the operation, this is closed with Tissuecoll®. To prevent shrinkage and scarring, cycling of the bladder has to start immediately after detrusorectomy. This can be done by maintaining a 20-cm H2O pressure on day 1, 30 cm on day 2, followed by clamping the catheter on day 3 for 2 h, and finally by opening the catheter every 3 h to empty the bladder on following days. In this way, optimal expansion of the detrusorectomized bladder can be obtained [21]. Several authors have reported success by expanding the bladder over a balloon for several days while ensuring drainage of urine by ureteral catheters. We have no experience with this procedure but assume it could work well if there is leakage. Others have successfully covered the bare part of the mucosa with a demucolized patch of sigmoid colon. Covering with peritoneum or omentum has been reported to fail.
Fig. 2The bladder can be augmented by removing the detrusor muscle. A sling is used to improve bladder outlet resistance
Clam cystoplasty
Clam cystoplasty (Fig. 3) is indicated when the bladder capacity is too small to reach acceptable numbers of catheterization per day and/or end-filling pressures are too high to be safe for the upper tracts. Clam cystoplasty is performed with either ileum or colon. In general, 25 cm of ileum are used, opened antimesenterically, and constructed into a U-shaped cap. The last 20 cm of the ileum are not used, to prevent malabsorption of vitamins. If there is a short ileal mesentery, the sigmoid colon can easily be used. It is important to avoid the formation of an hourglass bladder by opening the clam anteriorly up to the bladder neck and posteriorly up to the trigone. In children, we prefer to bring the augmented bladder extraperitoneally by closing the peritoneum around the vascular pedicle. This extraperitonealization of the bladder may initially make it more difficult to reach sufficient bladder capacity, but it seems to reduce the risk of spontaneous perforation of the bladder, which is a prominent risk in children because of their tendency toward bad CIC compliance during puberty. During a period of several years, we had two spontaneously leaking ileal bladders out of six that had not been placed extraperitoneally, and no spontaneously leaking/rupture in more than 40 other patients with extraperitoneal ileal bladder.
Fig. 3The bladder can be augmented by using a bowel segment
Bowel management and surgery
For the first 2 years of life, a wait-and-see policy is adopted in bowel management, often supported by chronic use of laxatives. At the age of 3 years, bowel management can be performed successfully in the vast majority of patients with retrograde colonic enemas. The rectum is filled with 20 ml/kg tap water through a plastic cone that passes approximately 2 cm into the anus. In the rare case where patients have trouble emptying their rectums with retrograde enemas, we offer an antegrade colonic enema stoma [29, 30]. A patient’s choice can be an indication for an antegrade colonic enema stoma. As a separate procedure, the simplest way to carry out an antegrade colonic enema stoma is to use laparoscopy to bring the tip of the appendix to the abdominal skin (Fig. 4). Alternatives are an open procedure with open abdomen for other surgery or, in the absence of an appendix, to create a transverse tube from the colon (left or right) and a submucosal tunnel to prevent leakage. Many pediatric surgeons and pediatric gastroenterologists have had good experiences with several types of buttons that are put into the colon.
Fig. 4The appendix can be used to make an antegrade colonic enema stoma
If these procedures are carried out, treatment of spina bifida patients can be very successful. In our experience between 1988 and 2001, the incidence of renal scarring in 144 patients was 2.1%, and urinary dryness in patients who opted to be dry was nearly 80% [14].
Surgery to improve sexuality in male patients
Sexuality can be frustrating for male spina bifida patients, because in most cases, they can have intercourse but penis sensibility is absent. To overcome this, in patients with a lesion under the level of L1, we have connected the ilioinguinal nerve with the dorsal nerve of the penis, resulting in glans sensibility and erogenous feeling in most patients. Patients report a positive effect on sexuality. Our experience with the first three patients has been published, and by now, of 15 cases operated, 12 report normal sensibility of the glans penis [31].
Conclusion
Kidney-function preservation and early urinary dryness are important factors for optimal quality of life for spina bifida patients. Another important factor is patient independence regarding his or her bladder and bowel management. For optimal treatment of this difficult group of patients, a multidisciplinary team is needed consisting of members from all the necessary medical specialties, including rehabilitation specialists, physical therapists, specialized nurses, and social workers.
Questions
(Answers appear following reference list)
Concerning renal scarring and renal failure in spina bifida literature:
Reported death rate due to renal failure is up to 20% in the first year of lifeReported renal failure rate is up to 20% in the first year of lifeReported death rate due to renal failure is up to 20% in pubertyReported renal failure rate is up to 20% in pubertyConcerning clean intermittent catheterization (CIC):
CIC is best started immediately after closure of the spinal defectCIC is best started immediately after the age of 8–9 yearsCIC is best started not earlier than after bladder neck surgeryCIC is best started not earlier than after several urinary infections and reported renal scarringInfection prophylaxis in spina bifida patients:
All patients need low-dose chemoprophylaxisFifteen percent of all patients need low-dose chemoprophylaxisScientific proof of the need for infection prophylaxis is still lackingNo patients need low-dose chemoprophylaxisIn case of hyperactive detrusor muscle in a patient with spina bifida:
Central side-effects occur less frequently if antimuscarinic therapy is administered orallyAntimuscarinic therapy is the gold standard for pharmaceutical therapyRepeated injection therapy of the bladder with only 3 U of botulinum toxin can be an alternative to antimuscarinic therapyAntimuscarinic therapy has positive effects on perspiration and body-temperature regulationIn modern management of spina bifida, endpoint targets are:
Kidney-function preservationDrynessFecal continenceAll the above
Electronic supplementary material
Below is the link to the electronic supplementary material.
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spina bifida
incontinence
renal function
dryness
antimuscarinic
bladder augmentation
surgical treatment
bladder-neck sling


SYD1/444: Assessing the Readership of the UK National Database of Telemedicine

Introduction The National Database of Telemedicine (NDTM) is a Web site containing information resources on UK telemedicine projects and related work. Its purpose is to provide a source of information to anyone researching the field or proposing a trial or a larger scale implementation of Telemedicine. The NDTM Web site was launched on 27th October 1998 and publicised extensively. Before and after its launch, the Web site has been kept up to date with information about new projects and modifications to the details kept about existing ones. It is clearly important for such a resource to keep track of who is reading it. We may need to tailor information to a particular audience, or bring the Web site to the attention of people who may not yet have found it. This paper describes a mechanism for tracking usage of the Web site that provides more information than conventional approaches.

telemedicine
internet
hypermedia
readership analysis


The first demonstration of lactic acid in human blood in shock by Johann Joseph Scherer (1814–1869) in January 1843

Lactic acid was first found and described in sour milk by Karl Wilhelm Scheele (1742–1786) in 1780. The German physician–chemist Johann Joseph Scherer (1841–1869) demonstrated the occurrence of lactic acid in human blood under pathological conditions in 1843 and 1851. In this article we honour the forgotten observations by Scherer and describe the influence of Scherer's finding on further research on lactic acid at the end of the 19th century. We conclude that Scherer's 1843 case reports should be cited as the first description of lactic acid in human blood after death and also as the first demonstration of lactic acid as a pathological finding in septic and haemorrhagic shock. Carl Folwarczny was, in 1858, the first to demonstrate lactic acid in blood in a living patient.
Introduction
Lactic acid was first found and described in sour milk by the Swedish chemist Karl Wilhelm Scheele (1742–1786) in 1780 [1]. The Swedish chemist Jöns Jakob Berzelius (1779–1848) found lactic acid in fluid extracted from meat in 1808 [2, 3], and the German chemist Justus von Liebig (1803–1873), who established the world's first school of chemistry at Giessen, proved that lactic acid was always present in muscular tissue of dead organisms [4]. In 1859, Emil Heinrich du Bois-Reymond (1818–1896) published several articles on the influence of lactic acid on muscle contraction [5–9]. Araki and Zillessen found that if they interrupted oxygen supply to muscles in mammals and birds, lactic acid was formed and increased [10–14]. This was the first demonstration of the relationship between tissue hypoxia and the formation of lactate. The occurrence of increased lactic acid in blood (hyperlactataemia) nowadays reflects severe illness, in which the increased blood lactate levels may result from both anaerobic and aerobic production or from a decreased clearance.
It was the German physician–chemist Johann Joseph Scherer who first demonstrated the occurrence of lactic acid in human blood under pathological conditions after death in 1843 and 1851 [15, 17], and Carl Folwarczny in 1858 who first demonstrated lactic acid in blood of a living patient. In this article we wish to honour Scherer's forgotten observations and describe the influence of his finding on further research on lactic acid at the end of the 19th century.
Biography of Johann Joseph Scherer
Born on 18 March 1814 in Aschaffenburg, Germany, Scherer studied medicine, chemistry, geology and mineralogy at the university of Würzburg between 1833 and 1836. He obtained his PhD in medicine and surgery in 1838 with a thesis entitled “Versuche über die Wirkung einiger Gifte auf verscheidene Thierclassen” (Experiments on the action of some poisons on several classes of animals). He practised medicine in Wipfeld, but inspired by the chemist Ernst von Bibra (1806–1878) he completed his studies in chemistry at the University of Munich between 1838–1840 [18]. In 1840 he was employed at the laboratory of Justus Liebig at Giessen, and became professor at the medical faculty in 1842, professor of organic chemistry in 1847, and later professor of general, anorganic and pharmaceutical chemistry. His work especially concerned quantitative research on blood and urine in pathological conditions. In 1843 he published his book ‘Chemische und Mikroskopische Untersuchungen zur Pathologie angestellt an den Kliniken des Julius-Hospitales zu Würzburg’ (Chemical and microscopic investigations of pathology carried out at the Julius Clinic at Würzburg) [15] (Fig. 1), in which he described 72 case reports, giving details on clinical course, diagnosis, and results obtained during autopsy and analysis of body fluids. Scherer died on 17 February 1869 [18].
Fig. 1Title page of Scherer's 1843 book
The 1843 cases
In one chapter in his 1843 book entitled 'Untersuchungen von krankhaften Stoffen bei der im Winter 1842–1843 in Würzburg und der Umgegend herrschenden Puerperal-Fieber-Epidemie' (Investigations of pathological substances obtained during the epidemic of puerperal fever which occurred in the winter of 1842–1843 in and around Würzburg) Scherer described the cases of seven young women who all died peripartum.
One of the women, the 23-year-old primipara Eva Rumpel, gave birth to a healthy child on 9 January 1843. The same night she developed a painfully swollen abdomen and became ill, feverish, and sweaty, with rapid pulse and severe thirst. The initiated treatment was bloodletting and clystering. The next evening she deteriorated, became delirious, with anxious breathing, a tense abdomen, cold extremities and rapid pulse, finally losing consciousness. Again, bloodletting followed. At 4:30 a.m., 36 h after the onset of the first symptoms, she died. During autopsy, severe purulent endometritis, vaginal pus, pulmonary oedema, and shock liver and shock spleen were found. The blood that was obtained directly from the heart was chemically analysed, in which lactic acid was found. Most likely this unfortunate woman had died from a fulminant septic shock caused by group A haemolytic streptococci (Streptococcus pyogenes). Scherer diagnosed this case as perimetritis with secondary peritonitis.
Another patient, the 28-year-old, 7 months pregnant (second pregnancy) Margaretha Glück, was, after being icteric, nauseous, vomiting and complaining about epigastric pain for 8 days, admitted to the lying-in birth clinic on 6 February 1843. Four days later she was transferred to the hospital with severe nosebleeds and generalised exanthema or purpura. In the evening she suffered from severe gastric bleeding and epistaxis, showing rapid pulse, cold extremities and dizziness. The next morning, she was transferred back to the birth clinic, where she gave birth to a premature child (30 weeks) and suffered from a severe post-partum fluxus. She was again transferred to the hospital with the following symptoms: cold clammy skin, tachycardia, severe lochia and persistent exanthema or purpura, but without signs of an acute abdomen. During the night of February 11, she became aphasic and restless, followed by chills and profound sweating. On the morning of February 13, she further deteriorated and bilirubinuria was detected. The next day she was comatose, finally developed rattling breathing and convulsions. Death occurred during the following night. Autopsy revealed a small intracerebral haematoma, normal lungs without pulmonary oedema, ascites and an anaemic, foul smelling uterus filled with purulent and decayed tissue and pus. Blood was also obtained directly from the heart during autopsy and lactic acid was found.
In this case we could think of a haemorrhagic shock and cerebral haemorrhage due to clotting disorders possibly resulting from either acute fatty liver of pregnancy/HELLP syndrome, idiopathic thrombocytopenic purpura, thrombotic microangiopathy (TTP/HUS) or DIC. The case was most likely complicated by a sepsis (endometritis). Scherer himself diagnosed this case as septic endometritis.
In the conclusions of his 1843 book, Scherer attached high importance to the fact that he found lactic acid in cases of puerperal fever, which he had not found before in healthy persons. He held the opinion that lactic acid was formed in blood during bodily deterioration in severe diseases like puerperal fever. Lactic acid was thus described for the first time in human blood and was demonstrated for the first time as a symptom of septic and haemorrhagic shock.
In the same period a junior obstetrician in Vienna, Ignaz Philipp Semmelweis (1818–1865), discovered in 1847 that physicians carried infectious particles on their hands from the mortuary to the obstetrical clinic, causing puerperal fever and puerperal sepsis, and he introduced a successful method for its prevention. Louis Pasteur (1822–1894) found in 1879 that infection with streptococci was the most important cause of puerperal fever [16].
The 1851 article
Scherer worked closely with the famous pathologist Rudolf Virchow (1821–1902) on several projects (Fig. 2). In 1851 Virchow performed an autopsy on a patient who had died from leukaemia and offered Scherer blood from this patient for analysis. The results of this analysis were published the same year in the ‘Verhandlungen der Physikalisch-Medicinischen Gesellschaft in Würzburg’  [17]. Virchow and Scherer had previously studied the spleens of patients who died from leukaemia, and were curious if they could find the same results in the blood. Scherer reached the conclusion that: the blood of this patient contains: “Ameisensäure, Essigsäure und Milchsäure, die gleichfalls von mir schon früher als in der Milzflüssigkeit vorkommend bezeichnet wurden” (Formic acid, acetic acid, and lactic acid, as also found by me previously in fluids from the spleen).
Fig. 2Johann Joseph Scherer (left) and Rudolf Virchow (right) in 1849
Further research
Scherer's observations inspired others to conduct further research, primarily in patients with leukaemia [19–22], but also in patients with other conditions and diseases and in animal experiments with dogs and rabbits [23]. While Scherer found lactic acid in blood obtained after death during autopsy, Mosler and Körner [19] mention an observation made by Carl Folwarczny, published in the Allgemeinen Wiener Medicinischen Zeitung in 1858, where blood was withdrawn from a leukaemia patient during life, analysed according to Scherer's method, and found positive for lactic acid. In addition, Carl Folwarczny described in 1863 in his 'Handbuch der Physiologischen Chemie' [24] that lactic acid can be found in the blood of patients with leukaemia, septicaemia (pyaemia) and in conditions leading to septicaemia like puerperal fever, the latter probably after Scherer's observations.
In an extensive article, the Berliner physician Georg Salomon [25], who had serious doubts that the occurrence of lactic acid in blood was mostly related to leukaemia, proved in 1878 that lactic acid was also present in the blood of patients who were suffering and died from other diseases. He studied blood obtained during autopsy from cadavers, but also blood from patients obtained by bloodletting or cupping, and in some cases he compared the blood before and after death. He was able to demonstrate lactic acid in the blood of patients suffering from leukaemia, (pernicious) anaemia, congestive heart failure, chronic obstructive pulmonary disease, pleuritis, pericarditis, pneumonia and several solid malignant tumours.
Gaglio [26] is often erroneously mentioned as the first author to find lactic acid in blood [27–29]. He was able to demonstrate lactic acid in fresh arterial blood withdrawn from dogs and rabbits after bloodletting. Berlinerblau [30] confirmed these observations in mammalian and venous human blood. Both Gaglio and Berlinerblau, however, neglected previous research, as indignantly described by Salomon in 1888 [“Ich erlaube mir, den Inhalt meiner Arbeiten, die von Gaglio nur ganz flüchtig, von Berlinerblau gar nicht berührt sind, in Kürze zu reproduciren” (I take the liberty of summarizing the contents of my work, which was mentioned only briefly by Gaglio and not at all by Berlinerblau)] [31].
The Japanese chemist Trasaburo Araki showed that the amount of lactic acid in exhausted muscle results from muscle activation [11]. Irisawa [32], inspired by the results obtained by Salomon and Gaglio, obtained fresh blood of 11 dying patients with serious conditions. In six cases he found hyperlactataemia, in four cases normal values. He speculated on the aetiology of hyperlactataemia, the most plausible cause being the severe hypoxia during the dying process. In an experiment in which he made a dog anaemic for several days, he found a rise in lactic acid levels during the time leading up to death.
In Cambridge (UK), Walter Morley Fletcher (1873–1933) and Frederick Gowland Hopkins (1861–1947) worked together on the metabolic changes occurring in muscular contractions and rigor mortis under anaerobic conditions, and found that lactate was the product of carbohydrate metabolism [33]. Their classic 1907 paper demonstrated rigorously that muscle contraction is accompanied by the anaerobic formation of lactic acid, which is removed aerobically, at a rate depending on the level of exposure to oxygen [34].
Poul Astrup and John Severingshaus mentioned Scherer's 1851 article as first demonstration of lactic acid in blood, but overlooked the 1843 cases and Folwarczny's work [35]. In conclusion, Scherer's 1843 case reports [15] should be cited as the first description of lactic acid in human blood and also as the first demonstration of lactic acid as a pathological finding in septic and haemorrhagic shock. Folwarczny, in 1858, was the first to demonstrate lactic acid in blood in a living patient.

lactic acid
shock
johann joseph scherer
lactate
leukaemia
historical article