Resection of cerebral arteriovenous malformations (AVM) is technically demanding because of size, eloquent location or diffuse nidus. Controlled arterial hypotension (CAH) could facilitate haemostasis. We performed a study to characterize the duration and degree of CAH and to investigate its association with blood loss and outcome.We retrospectively analysed intraoperative arterial blood pressure of 56 patients that underwent AVM-resection performed by the same neurosurgeon between 2003 and 2012. Degree of CAH, AVM size, grading and neurological outcome were studied. Patients were divided into two groups, depending on whether CAH was performed (hypotension group) or not (control group).p <  0.001) longer, and median blood loss (500 ml) was significantly (p = 0.002) higher than in the control group . No case fatalities occurred. CAH was associated with a higher amount of postoperative neurological deficits.The hypotension group consisted of 28 patients, which presented with riskier to treat AVMs and a higher Spetzler-Martin grading. CAH was achieved by application of urapidil, increasing anaesthetic depth or a combination thereof. Systolic and mean arterial blood pressure were lowered to 82 ± 7 and 57 ± 7 mmHg, respectively, for a median duration of 58 min . In the hypotension group, duration of surgery (4.4 ± 1.3 h) was significantly (Whether CAH caused neurological deficits or prevented worse outcomes could be clarified by a prospective randomised study, which is regarded as ethically problematic in the context of bleeding. CAH should only be used after strict indication and should be applied as mild and short as possible. Blood flow through a vessel is determined by both perfusion pressure and vessel diameter. Whenever a vessel is injured by surgery, it will be occluded by coagulation, ligation or clipping. However, some vessels cannot be occluded immediately which could result in profound blood loss. In these instances, a lowering of perfusion pressure will reduce blood loss and allows the surgeon a better view (and control) of the bleeding source. As a consequence, controlled arterial hypotension (CAH), defined as a lowering of arterial blood pressure (ABP) by pharmacologic measures, is an established procedure  in ophthFor cerebral vessels, the pathophysiology is at least partially different, since cerebral autoregulation will maintain cerebral blood flow (CBF) despite lowering of arterial blood pressure. Only if ABP drops below the lower threshold of cerebral autoregulation, then CBF will decrease and blood loss through an injured cerebral vessel will be reduced. Anaesthesia affects cerebral autoregulation depending on the hypnotic drugs used: It is maintained during propofol anaesthesia but impaired when using volatile anaesthetics in a dose depending fashion: While cerebral autoregulation is preserved during concentrations up to 1 MAC, it is impaired at higher concentrations (> 1.5 MAC) .Cerebral arteriovenous malformations (AVM) are vascular abnormalities characterized by a direct connection via pathological vessels between arteries and veins without a normal interposed capillary bed. Therefore, vessel resistance is reduced resulting in a low perfusion pressure but high blood flow through the AVM. The autoregulatory curve of the adjacent brain tissue is shifted to the left , 22 to cThe different anatomical structure of AVMs makes them fragile and difficult or impossible to occlude by coagulation. In addition, cerebral autoregulation is absent in these vessels, which makes controlled arterial hypotension an effective measure to reduce blood flow and blood loss during AVM resection , 17, 24.There is a gap of knowledge about what degree of CAH can be considered safe. Therefore, we analysed the extent of the reduction in blood pressure, as primary objective. Secondary objectives were the duration of CAH, the methods used to induce and terminate CAH, blood loss and neurological outcome. We hypothesized, that the application of CAH does not impair the neurological outcome.All patients who ever harboured an AVM that was removed by the senior neurosurgeon (J.S.) at our institution between 1990 and 2012 were included. Patients for whom no anaesthetic protocol was available were excluded. Based on the anaesthesia records, the intraoperative course of ABP, blood loss, duration of surgery and the methods used to induce, maintain and terminate CAH were studied. Additional information with respect to clinical presentation on admission, AVM characteristics according to the Spetzler-Martin Grading , and outEither a balanced or a total intravenous anaesthesia was performed. All patients received cis-atracurium and remifentanil for muscle relaxation and antinociception, respectively. Patients were intubated and mechanically ventilated. Arterial blood pressure was determined invasively by a radial arterial line, which was referenced to the level of the right cardiac atrium. Any substantial blood loss was replaced by packed red blood cells, and haemoglobin concentration was determined via arterial blood gas analysis whenever it was deemed necessary. The details of the surgical technique are described elsewhere . The neuThe patient records were searched for evidence of acute renal failure or acute myocardial infarction in the postoperative course. The former was defined as the occurrence of oliguria or the need to perform a renal replacement therapy. The latter was assumed if a cardiologist made the corresponding diagnosis based on clinical symptoms as well as ECG and troponin changes. Neurological complications were defined as occurrence of any non-pre-existing intracerebral haemorrhage or neurological deficit in terms of motor, sensory, visual, or speech deficit. Neurological outcome was assessed immediately postoperative until discharge, as well as 6 months thereafter using the modified Rankin Scale .p <  0.05. To identify predictors of outcome, a Receiver Operating Characteristic (ROC) as well as a Stepwise Regression Analysis were performed.Statistical analysis was performed using SigmaPlot . Data are shown as mean ± standard deviation in case of normal distribution or as median  otherwise. Groups were compared using the unpaired t-test or the Mann-Whitney Rank Sum Test, respectively, and statistical significance was assumed at a p = 0.025) lower modified Rankin scale grade (mRS) on admission  and tended to be more often without disability  than the control group patients (Table p = 0.027) and Spetzler-Martin grading  than control patients (Table p = 0.001) more often in the hypotension (18 patients) than in the control group (5 patients).Of the 226 patients operated on by the senior neurosurgeon JS, 67 operations took place during the period (from 2003) when anaesthesia records were available. In 11 patients in the AVM database, no corresponding anaesthesia protocol could be found, so that 56 patients were available for the final analysis. Patient’s age ranged from 11 to 61 years (mean age = 34.3 ± 12.5 years). Twenty-one patients presented with a ruptured AVM, and 35 with an unruptured malformation. Preoperative embolization was used as an adjunct in seven of our patients. The hypotension and control group consisted of 28 patients each, and did not differ with respect to age, gender, body weight, height and the proportion of ruptured AVMs (Table n = 46) or propofol (n = 10).During CAH, the systolic and mean arterial blood pressure (MABP) were lowered to 82 ± 7 and 57 ± 7 mmHg, respectively, for a duration of 58 26; 107] minutes. At the end of anaesthesia, MABP was lower in the hypotension group (71 ± 10 versus 78 ± 10 mmHg); otherwise, there was no difference in ABP between groups  and a positive correlation between the size of the AVM and the duration of hypotension .We found a negative correlation between the Spetzler-Martin grading and the mean ABP (n = 11 patients) or in combination with a deepening of general anaesthesia (n = 6). In another 3 patients, urapidil was combined with one or two other antihypertensives. In further 4 patients, CAH was induced by deepening of general anaesthesia without application of antihypertensive drugs. In 4 cases, no clear method could be identified.CAH was induced most often by urapidil, either as a sole agent .n = 12) terminated by administration of akrinor, which is a mixture of 200 mg cafedrine and 10 mg theodrenaline. In addition, CAH was finished by using akrinor combined with noradrenaline (n = 2), stopping the administration of urapidil (n = 3) or nitroglycerine (n = 1), a reduction of general anaesthesia (n = 4) or a combination of akrinor and reduction of general anaesthesia (n = 1). In three cases, no clear method could be identified, and in two patients hypotension was continued beyond the end of surgery. None of the patients required catecholamines to support blood pressure at the end of surgery or during transfer to intensive care. For the postoperative period of 24 h, an upper limit for systolic blood pressure was set in 15 patients, with a target of 120, 100 and 90 mmHg in 3, 10, and 2 patients, respectively.CAH was most frequently (p = 0.002) more blood loss  in the hypotension than in the control group , with significantly  and the duration of CAH  was observed.In the hypotension group, the duration of surgery and anaesthesia was significantly longer (by 66 min) as compared to the control group Table . Follow p = 0.082; Fig. p = 0.003; Fig. p = 0.017). In addition, patients with postoperative hemiparesis showed a significant lower mean ABP  and CAH was approximately 1 hour longer  longer in case of postoperative hemiparesis (2.1 ± 1.7 h vs. 1.0 ± 0.7 h).Comparing patients with and without postoperative neurological deficits, the former had higher values on the Spetzler-Martin scale , followed by the duration of CAH  and the product of duration and extent of CAH . In contrast, the AUC for Spetzler-Martin grading (0.63) was not significant different from 0.5  of CAH and neurological outcome suggests a relationship between hypotension and outcome. Both depth and duration of CAH also turned out to be predictors for the incidence of neurological deficits and seemed to have more influence than the location, graduation or size of the AVM. However, these findings cannot distinguish whether there is an association or a causal relationship between hypotension and outcome. To clarify this matter, a prospective randomized-controlled study would be necessary. However, such a study would likely be considered unethical since the non-CAH group would be at an increased risk of bleeding and adverse surgical conditions.The AVM serves as a low-pressure, high-flow shunt, so that cerebral ischaemia can develop in the surrounding tissue due to the resulting arterial hypotension and steal phenomena . TherefoThe MABP of 57 ± 7 mmHg observed during hypotension in our study is well below the lower threshold of cerebral autoregulation, which is unknown in a given patient but commonly assumed to be around 70 mmHg in the normotensive adult, although autoregulation limits are reported to be subject to interindividual variability , 8. We cA leftward shift of the autoregulation curve in the brain tissue around the AVM has been reported, predisposing these patients to postoperative hyperperfusion while providing some resistance against hypoperfusion , 22. MorThe patient cohorts were not comparable with respect to their AVMs: Patients treated with CAH showed higher Spetzler-Martin grading mainly due to their larger AVM size. We can therefore assume that the patients in the hypotension group suffered from AVMs, which were more difficult to resect with a higher risk of neurological complications. In fact, because of the expected difficulty, a higher incidence of side effects was anticipated, with these anticipated difficulties being the main reason for wishing induced hypotension. In general, there were no neurological deficits when the MABP was > 75 mmHg regardless of the Spetzler-Martin grading.Since all of our patients were operated by the same neurosurgeon, differences in the duration of surgery and in blood loss may be regarded as indicators for the difficulty/complexity of AVM-resection. Surgery in the CAH group lasted on average 66 min longer and was associated with higher blood loss than in the control group, suggesting a more difficult/complex resection in the hypotension group. This can be attributed to the fact that the neurosurgeon wished for the initiation of CAH because he experienced or anticipated difficulties for example due to bleeding. In the vast majority of patients, CAH was not started as a reaction to diffuse bleeding, but it was a preoperative decision in nearly all cases. Usually, the ABP range was already decided by anaesthetist and neurosurgeon prior to skin incision. Due to the large experience of the surgeon, it was usually no problem to decide which case might pose difficulties with haemostasis. In general, CAH was not a panic reaction to some surprising event but a well-planned resection policy.AVM-vessels are fragile and difficult to coagulate . AccordiAVM resection is associated with considerable morbidity and mortality, with higher Martin-Spetzler grading resulting in worse outcomes , 37. No The decision for or against CAH was made jointly by neuroanaesthetist and neurosurgeon based on the shared responsibility for the patient. Certainly, blood pressure management is the responsibility of the anaesthetist and in many countries, it is therefore unusual for the surgeon to be involved in blood pressure management. Especially in the situation of threatened or actual bleeding during resection of AV malformations, we believe that the team decision has proven its worth at our hospital.No method to induce or terminate controlled arterial hypotension proved superior compared to the other methods used in this study. Although CAH is a routine task performed by anaesthesiologists, its implementation is by no means trivial. MABP was lowered to some extent in all patients of the hypotension group, but the target MABP was never reached in 18% of patients. Despite the administration of highly effective vasoactive drugs, precise control of blood pressure is often difficult, especially if a too pronounced reduction in blood pressure is to be avoided. No consensus exists in the literature as to which agents should be used , but froNo consensus exists as to which target MABP should be achieved during CAH , 41. HerStudies on perioperative myocardial infarction have brought the intraoperative course of blood pressure more into the focus of anaesthesiologists. Accordingly, intraoperative MABP below 55–70 mmHg is associated with myocardial injury, myocardial infarction, renal injury, and death , 31, 40.Since cerebral oxygen supply is determined by cerebral blood flow, haemoglobin concentration and blood oxygen saturation, both anaemia and hypoxaemia could contribute to cerebral hypoxia. No hypoxia but some “mild” degree of anaemia (11.7 ± 2.1 g/dl) occurred in our patients despite transfusion of packed red blood cells. We believe that we have performed blood gas analyses often enough to detect the nadir of Hb concentration and identified the lowest intraoperative Hb concentration as an independent predictor of long-term outcome.A major strength of our study is that surgery was performed by a single surgeon only, thus eliminating intersubject (perhaps better inter-surgeon) variability in outcome. However, it is limited by the retrospective design and sample size. The archived anaesthesia protocols only go back to the year 2003, so only 56 of the 226 patients operated on in Bonn since 1990 could be included. Hence, results should be interpreted with caution and should not easily be generalized.The blood pressure in the postoperative course can also influence the treatment outcome. For example, postoperative increases in blood pressure can lead to neurological deterioration with cerebral oedema, based on the Normal Perfusion Pressure Breakthrough Theory . This haAge is a predictor for outcome in AVM . Since aCurrent management options for AVMs include microsurgical resection, embolization, stereotactic radiosurgery, and medical treatment  , wherebyIn case of expected difficulties during AVM-resection, a team decision to apply CAH can be made. However, the outcomes in our patients operated with CAH are worse than in those operated without CAH. It remains unclear, whether this reflects (only) the complexity of the case, or is  an effect of the CAH. Therefore, CAH should only be applied with strict indications and as mild and short as possible.


Resistant hypertension is common and known to be a risk factor for cardiovascular events, including stroke, myocardial infarction, heart failure, and cardiovascular mortality, as well as adverse renal events, including chronic kidney disease and end-stage kidney disease. This review will discuss the definition of resistant hypertension as well as the most recent evidence regarding its diagnosis, evaluation, and management. The issue of medication non-adherence and its association with apparent treatment-resistant hypertension will be addressed. Non-pharmacological interventions for the treatment of resistant hypertension will be reviewed. Particular emphasis will be placed on pharmacological interventions, highlighting the role of mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 inhibitors and device therapy, including renal denervation, baroreceptor activation or modulation, and central arteriovenous fistula creation. Resistant hypertension (RH) is usually defined as blood pressure (BP) that remains above guideline-specified targets despite the use of three or more antihypertensive agents at optimal or maximally tolerated doses, with one of those agents preferably being a diuretic see . It is nThe first step in the management of RH is to exclude apparent treatment-RH, which may be caused by the white-coat effect, medication non-adherence, and therapeutic inertia. Furthermore, evaluation for secondary causes of hypertension, most commonly primary aldosteronism, should also be conducted. Only after careful exclusion of these factors can true RH be diagnosed. Based on a recent systematic review , the preBoth office and out-of-office BP measurements can be used for the diagnosis of hypertension. The cutoffs for diagnosis vary with the measurement method used. Furthermore, BP targets also vary depending on the patient’s comorbidities and estimated CV risk . TherefoNot only are accurate and standardized office BP measurements important in the diagnosis of RH, out-of-office measurements, usually with a 24-h ambulatory blood pressure monitoring (ABPM), are crucial to rule out white-coat hypertension , which, in one study , was preDrug profiles should be reviewed for drugs known to cause increased BP, and those should be discontinued wherever possible prior to the diagnosis of RH. Additionally, clinical (or therapeutic) inertia, defined as the failure of health-care providers to initiate or intensify therapy when therapeutic goals are not reached , is fairMedication non-adherence is more common in apparent treatment-RH than is usually appreciated. In the published literature, its prevalence has been estimated to vary from 3 to 86% based on individual studies from a systematic review . It can Several drugs and substances can raise BP, and whenever possible, their use should be decreased or stopped. Common culprits include calcineurin inhibitors, licorice, erythropoietin, tyrosine kinase inhibitors, non-steroidal anti-inflammatory drugs, cocaine, amphetamines, oral contraceptive agents, other sympathomimetics, and corticosteroids. The commonest causes of secondary hypertension are primary aldosteronism, followed by renovascular hypertension. Other less common causes would include phaeochromocytoma, paragangliomas, and other endocrine causes of hypertension. Screening and workup for these conditions should follow the specific patient presentations.Patients with RH are heterogeneous from a pathophysiology perspective. A large component of these patients, even after excluding primary aldosteronism, have a low renin phenotype, and would respond to sodium restriction and escalation of natriuresis in some form. A smaller proportion may have a neurogenic component to hypertension, and may respond better to sympathetic blockade. Indeed, a condition labeled as ‘refractory hypertension’ has been described, which refers to patients whose BP is uncontrolled despite the use of four drugs, including a thiazide-like diuretic and spironolactone. In these patients, little evidence of volume expansion is seen, and the neurogenic component may be more important, and the use of sympatholytic agents may be more beneficial.Nonpharmacological interventions should be reviewed and reiterated as part of the management of RH. These include physical exercise, weight reduction, abstinence from alcohol or reduction in alcohol consumption, adherence to the Dietary Approaches to Stop Hypertension (DASH) diet, reduction in sodium intake, increase in dietary potassium intake , and stress management. These patients are often salt sensitive, and efforts to reduce salt intake even at this stage are useful. In a small crossover trial of 12 patients with RH, the baseline mean sodium intake was 195 mmol/day. On a 50 mmol/day diet, compared to 250 mmol/day, the office BP decreased by 22.7 mm Hg (systolic) and 9.1 mm Hg (diastolic).Measures to improve medication adherence and the elimination of drugs and substances known to increase BP should be undertaken where possible. Management of medication non-adherence may include interventions such as reminders and pill packs as well as exploration into the reasons underlying non-adherence, which may include specific patient motives and beliefs pertaining to hypertension and its management .Pharmacological management of hypertension traditionally includes the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide-like diuretics as first-line. This is commonly referred to as the A-C-D combination. The definition of RH requires three drugs at optimal doses including a diuretic, and would usually mean including antihypertensives from the A-C-D combination.2 = 0.13, p < 0.0001). However, the superior benefits of BP lowering with spironolactone in PATHWAY-2 extended across the range of renin levels except amongst those with very high renin levels where beta blockers were more effective.RH has been associated with inappropriately elevated aldosterone levels and activation of the sympathetic nervous system . SeveralAs is apparent, the RCTs discussed in the previous section are all of a short duration, up to three months, and hence there are scant data on the benefit of specific pharmacotherapies on clinically relevant outcomes . An epidemiological study of about 9000 RH patients used propensity score matching to compare CV outcomes with aldosterone antagonists as reference compared to alpha and beta adrenergic antagonists. In this study, the latter two classes had a lower risk of adverse CV outcomes, with an HR of 0.68 for alpha and an HR of 0.81 for beta adrenergic antagonists, respectively. This result probably reflects residual confounding, but does not provide us confidence in the long term benefit of specific drug classes in RH. The Resistant Hypertension Optimal Treatment (ReHOT) trial included 187 patients with RHT randomized to spironolactone compared to clonidine as additional therapy. At three months, the mean change from baseline in office BP (in mm Hg) was similar between spironolactone (−15.1 for systolic BP and −7.7 for diastolic BP) and clonidine (−13.7 and −6.4 respectively). However the decrease in 24 h ABPM (in mm Hg) was greater with spironolactone (−11.8 for systolic BP and −6.3 for diastolic BP) than with clonidine (−7.3 and −3.9 respectively). Thus the overall literature supports that, following spironolactone, pharmacotherapy with the addition of alpha- and beta-adrenergic antagonists, or clonidine to the baseline regimen decreases BP significantly, with ongoing uncertainty about the superiority of specific drug classes for clinical outcomes.Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or flozins, are another class of medications that are increasingly being recognized and utilized not only for their glucose lowering efficacy, but also due to their recently demonstrated beneficial effects on CV and renal outcomes ,21,22,23p = 0.002) and mean 24-h diastolic BP by 2.9 mmHg  compared with placebo in patients with diabetes and uncontrolled nocturnal hypertension [p = 0.0025) in mean 24-h systolic BP and 7.43 mmHg  and 4.25 mmHg  in office systolic BP and diastolic BP, respectively, with Empagliflozin compared with placebo in African Americans with type 2 diabetes [The BP lowering effects of flozins, mainly empagliflozin, were especially pronounced in two specific populations of hypertensive patients, namely diabetics with lack of nocturnal dipping in BP and Black patients with type 2 diabetes. In a study by Kario et al., Empagliflozin reduced mean 24-h systolic BP by 7.7 mmHg  and diastolic BP by 1.7 mmHg (95% CI 0.9 to 2.5 mmHg). The proportion of patients with presumed RH that achieved a systolic BP < 130 mmHg was also higher with empagliflozin compared with placebo (38% vs. 26% at week 12 of follow-up). In this trial, the use of empagliflozin in presumed RH was also associated with a significant reduction in CV death, CV death or hospitalization for HF, and incident or progressive nephropathy. A major limitation of this study is that it is a post-hoc analysis and therefore does not consider factors such as medication adherence, clinical inertia, accurate and standardized BP measurements, and white-coat hypertension in the definition of presumed RH, which, as discussed above, are essential components of the evaluation of RH [post-hoc analysis of the CREDENCE trial [2), a sustained doubling of serum creatinine, or death caused by kidney or CV disease of 30% in the canagliflozin group compared with the placebo group (HR 0.70 (95% CI 0.59 to 0.82). Similar to the effect on systolic BP, this effect was consistent across all prespecified subgroups [The BP lowering effects of flozins especially in RH were examined in a study by Ferreira et al., a me study ,26. In tme study . 85.9% oon of RH . SecondlCE trial . In thisubgroups ,30. Of napparent RH, given the absence of ABPM as inclusion. Nevertheless, the clear outcome data support the use of flozins in RH when accompanied by standard indications for these drugs, such as DM, CKD, albuminuria, and/or HF.These data support the emerging and potential role of flozins in RH, however one should note that trials of flozins with clinical outcomes explicitly in the RH population have not been done. The data of clinical benefit cited above, even in subgroups from CV outcome trials, are in patients with The surgical interventions to reduce BP that have been investigated include lumbar sympathectomy, renal denervation, baroreceptor activation or modulation therapy, and central arteriovenous fistula creation. These interventions are summarized in Lumbar sympathectomy is of historical importance, since it was initially deployed when no effective treatment for hypertension existed. It effectively decreased BP (up to 70 mmHg in some cases), but was abandoned due to its association with serious side effects, including paralytic ileus, impotence, loss of sweating, loss of sensation, and death ,32, and p = 0.26). There was also no significant change in the 24-h ambulatory systolic BP between the two arms  [Renal denervation involves the ablation of sympathetic afferents in the renal artery, which in turn decreases efferent sympathetic tone, which is known to play a role in maintaining BP. Initial reports on the use of this technique showed effective reduction in BP, up to 20 to 30 mmHg, in patients with severe RH ,34. Howe = 0.98) . Potenti = 0.98) . More re = 0.98) ,37,38. Ip = 0.08). 54% of the patients in the BAT group were responders, compared with 46% in the control group, which was not statistically significant (p = 0.97). 25.5% of the study participants developed adverse events. The most frequent adverse event with this intervention was nerve injury at the time of device implantation with the first-generation device [clinicaltrials.gov: NCT03179800), and aims to evaluate the safety and effectiveness of the MobiusHD system on ambulatory BP in patients with RH. The CALM-START study is another prospective, randomized, double blind, sham-controlled study investigating the efficacy and safety of the MobiusHD system on ambulatory BP in patients with RH . The Barostim Neo System is a second-generation minimally invasive unilateral single electrode device that has been developed and is currently being investigated, although mostly in the HF population. No RCT-level data is available for this device in the RH population. However, two RCTs are currently under way. The Nordic BAT study is a randomized, double blind, parallel-design clinical trial which will include 100 patients with RH and will evaluate the effect of baroreceptor activation therapy on 24-h systolic ambulatory BP at eight months of follow-up compared with continuous pharmacotherapy, with secondary endpoints including effects of BAT on home BP, office BP, and autonomic function . The Economic Evaluation of Baroreceptor STIMulation for the Treatment of Resistant HyperTensioN (ESTIM-rHTN) study is another randomized open-label trial of BAT which is currently under way . This trial will compare the cost-effectiveness of BAT with usual care.Baroreceptor activation therapy (BAT) involves activation of the myogenic stretch reflex in the carotid body, which results in a reduction in central sympathetic activity and a lowering of BP. After an initial promising pilot RCT, the pivotal double blind Rheos RCT showed a mean decrease in office systolic BP of 16 +/− 29 mmHg compared with 9 +/− 29 mmHg in the control group with this technique at six months, but this was not statistically significant  and non-steroidal mineralocorticoid antagonists  have been approved for specific clinical indications, but may have BP lowering and clinical outcomes in the RH population worth testing. Additional agents such as aldosterone synthase inhibitors and endothelin antagonists are undergoing clinical trials and may provide more arrows in our pharmacological quiver. Most importantly, there are several questions that still need to be answered with clinical trials. The ACD combination being superior to other combinations has not been tested in a clinical trial, and it is possible that the incorporation of spironolactone, especially in the low renin setting, may be superior even as a first-line drug. The RH is common and known to be a risk factor for CV and renal events. The first step in its management includes ruling out apparent treatment-RH, which may be related to the white-coat effect, medication non-adherence, and therapeutic inertia. Evaluation for causes of secondary hypertension should also be performed in the appropriate clinical setting. Patients with suspected or confirmed RH are best managed by a hypertension specialist. The management of confirmed RH includes nonpharmacological interventions, with emphasis on strategies to improve medication adherence as indicated, and pharmacological interventions. The backbone of pharmacological management of RH involves the use of the A-C-D combination, followed by MRAs such as spironolactone. Newer class of drugs, such as flozins, show some promise in post-hoc analyses of trials. While device therapy  shows promise in clinical trials, no recommendations could be made for its use in this setting yet, but this remains an area of active investigation.


P = 0.023). The IOP measured at OCTA exam was significantly related to the width of the deep VD (P = 0.009). By contrast, average ganglion cell inner plexiform layer thickness (GCIPLT) was substantially related to the width of the superficial VD (P = 0.004). In logistic regression analysis, aging was noticeably associated with wider deep VD, whereas worse mean deviation (MD) had a significant association with wider superficial VD . In sum, while changes of the superficial layer seemed an overall ramification of glaucomatous damages, the deep layer was more likely to be affected by factors related to ocular microcirculation, such as IOPs and older age. Thus, looking into the deep vascular layer using OCTA could identify risk factors related to the disturbance in ocular microcirculation.We investigated the characteristics of localized vessel density defects (VD) either in the deep or superficial vascular layer of normal-tension glaucoma patients using optical coherence tomography angiography (OCTA). In this retrospective, cross-sectional study, 74 eyes with localized retinal nerve fiber layer (RNFL) defect were included. The relationships between the widths of the VD in the superficial and deep layer and ocular factors were evaluated. Eyes with greater deep VD were significantly older ( Generally, intraocular pressure (IOP) has been regarded one of the major risk factors for the mechanical stress, however, large, randomized clinical studies such as the Collaborative Normal Tension Glaucoma Study (CNTG) and the Early Manifest Glaucoma Trial (EMGT) showed that migraine, disc hemorrhages, or lower ocular systolic perfusion pressure affected substantially on progression of the disease3. Furthermore, precedent studies using fluorescein angiography found hypoperfusion in optic disc of glaucoma patients and suggested that their optic disc might have susceptible vasculature regardless of IOP elevation5. Other studies using color doppler imaging system found that decreased or impaired in retinal microcirculation and retrobulbar blood flow might be associated with glaucoma7.Glaucoma, a progressive optic neuropathy, is a result of irreversible but continuous loss of retinal ganglion cells and their axons due to mechanical stresses on lamina cribrosa9, superficial peripapillary10, macular11, and foveal avascular zone area12 was associated with severity of glaucoma. Nonetheless, superficial layers were only included in previous studies, and this might be due to the fact that superficial retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) are main sites experiencing glaucomatous damage, and therefore, the microcirculation of the deep layer might be less likely to be thwarted. In addition, deep layer of OCTA images might be hindered due to projection artefacts (PA)13. However, with the development of the PA removal software, the deep layer of OCTA images became involved in the evaluation15.Lately, optical coherence tomography angiography (OCTA) detecting blood flow through the motion contrast generated by red blood cells has been developed, and has been a useful implement for accessing microcirculation in peripapillary, macular, and choroid layers. According to studies via OCTA, blood circulation in various layers including optic nerve head16, and their subsequent study suggested that deep macular vessel density might be able to be a predictor of glaucomatous visual field (VF) progression related with vascular incompetence17.In terms of changes in the deep vascular layer, Jeon et al. found that deep macular vessel density was an independent risk factor of central visual function and retinal thickness thinningConsidering the fact that deep layer of the OCTA might reflect changes of microcirculation caused by glaucoma, it may be important to look into related factors to OCTA changes in both superficial and deep layers. Therefore, the aim of this study was to find out associated factors to VD at the site of localized RNFL defect in both superficial and deep layers and compare the features between patients with wider VD in the superficial or deep layers on OCTA.Initially, 194 eyes were recruited, however, eyes were excluded: 74 eyes due to less than 10° difference between the two layers, 33 eyes due to lack of presence of the VDs in the both layers, and 15 eyes whose image quality score less than 50. The rest of 72 eyes of 72 patients with NTG who satisfied the inclusion and exclusion criteria were included for further study.P, 0.023). Regarding the degree of visual field defects, the SVD group showed substantially progressed status not only in mean deviations (MD) but also in pattern standard deviation (PSD), and visual field index (VFI) . In addition, the DVD group showed a higher proportion of the paracentral VF defect, compared to the SVD group .Patient’s characteristics are in Table With regard to the OCT parameters Table , there wP, 0.004). MD and average RNFLT showed borderline correlation with the width of the superficial VD . Meanwhile, the IOP measured at the OCTA exam showed a significant correlation with the width of the deep VD , and baseline IOP was marginally correlated with the width of the deep VD . In Fig. 2, 0.045, P, 0.068, R2, 0.112, P, 0.04, respectively), yet these relationships were attenuated with the width of the deep VD . Nonetheless, the width of deep VD increases as baseline and measured IOP increases .The Pearson correlation analysis was performed between clinical parameters and the width of the VDs in the superficial and the deep layers in the total eyes Table . The aveP, 0.041), while the IOP factors including baseline and measured IOP, and central corneal thickness (CCT) showed significant correlations with the width of the deep VD .Further analyses were carried out with patients whose MDs were worse than − 3 dB and better than − 6 dB  in the univariate analysis, however, in the multivariate analysis, only the measured IOP showed a significant association . As for the width of the superficial VD  loss, and found that the angle was significantly correlated to the flow density. Additionally, the angle showed markable correlations with PSD, MD, and RNLFT. In our study, average GCIPLT was the most significantly correlated factor, while MD and average RNFLT had mere borderline correlations. These findings suggest that the width of the superficial VD has a potential of a morphological indicator which reflects the changes in glaucoma. The disparity in the correlations with VF indexes in these two studies, however, might be due to the fact that the recruitment of patients in our study was confined to MD >  − 6 dB.Previous studies have well shown that a plummet in ocular microvascular circulation is correlated to the status of the disease15. However, changes in the choroid layer would not be overlooked in light of the fact that insufficient blood supply at the level of lamina cribrosa is regarded as one of the main cause of glaucoma24. Additionally, the blood supply to prelaminar region of the ONH is mainly dependent on posterior ciliary arteries, which are mainly distributed in peripapillary choroid layer25.Up to now, most OCTA studies have been reluctant to scrutinize the relationships or changes in the deep layer, of which the majority lies below the INL, and extends to the Bruch’s membrane. This might be due to the fact that the blood flow signal is more likely to be lost in the deep layer and existence of the projection artifacts degrades the quality of the images28, to the best of our knowledge, this might be the first study that explored the relationship between the peripapillary deep layer and glaucomatous risk factors. There was a plethora of studies using OCT to evaluate the impact of glaucoma to the peripapillary choroid layer, yet no census has been established. Some reported that peripapillary choroidal thickness does not reflect the severity of glaucoma. Namely, no notable differences in the thickness were observed among controls, glaucoma suspect, POAG, NTG, and PACG31. Nonetheless, others claimed that the peripapillary choroidal thickness in glaucomatous eyes was obviously thinner than that in eyes of controls or glaucoma suspects34. Regarding the factors related to the width of deep VD, IOP was the most influential factor. In line with this finding, Ersoz et al.34 reported that higher IOP was significantly associated with the peripapillary choroidal thickness, while other parameters, including MD, RNFLT, and lamina and prelaminar thicknesses were not. According to Maul et al.29, the significant relationships were found between the peripapillary choroidal thickness and higher IOP, lower diastolic ocular and blood perfusion pressures. Based on the results, he suggested that thick choroid in eyes with higher blood pressure and low IOP was natural with the presence of increased choroidal blood volume with higher diastolic perfusion pressure. In this regard, although we did not measure blood pressure of the patients, we presume that alternations in IOP would affect tremendously to the choroidal circulations in the deep layer by modulating peripapillary choroidal thickness simultaneously. In the present study, baseline IOP with the borderline significance and the IOP measured at OCTA exam with substantial significance were found. In other words, compromised flow in the deep choroidal layer on OCTA around the optic disc due to high IOPs could affect the course of glaucoma and contribute to glaucoma progression.Though studies about peripapillary atrophy including choroidal microvascular dropout via OCTA were common29 had the same finding, yet the magnitude was more meager, compared to those of other variants. In contrast, instead of CCT, Park et al.32 found axial length was the significant determinant with peripapillary choroidal thickness, and other precedent researches36 suggesting that myopic NTG patients had thinner peripapillary choroidal thickness. However, compared to the patients’ average axial length in Park et al., our patients had longer axial length. Another study reported that CCT was found to be inversely related with macular choroidal thickness, but the multivariate model excluding axial length and anterior chamber depth (ACD) revealed that CCT had no significant correlation with choroidal thickness30. Accordingly, further exploration including collecting data of ACD would be necessary for clarification.In terms of CCT, based on the analysis of all eyes, it was not a critical factor for the width of the deep VD. Instead, in eyes with MD <  − 3 dB, thicker CCT had a significant association. Maul et al.37. Hirooka et al.35 also showed that age had a correlation with mean peripapillary choroidal thickness in the NTG patients. Histopathologic studies have shown that the vessel density and diameter in the choroid decline with aging39. Therefore, we hypothesize that the ramification of the compromised choroidal vasculature due to senile effects could be possibly presented as a wider width of the DVD.With respect to age, the mean of the DVD group was remarkably older than that of the SVD group, and aging was significantly associated with wider DVD. The study, including normal Chinese population, found that the average peripapillary choroidal thickness decreased linearly with age40. Similarly, there was a finding that medically treated NTG eyes that experienced severe fluctuation in the 24-h ocular perfusion pressure had faster paracentral VF defect progression than eyes with stable pressure41. Nevertheless, some studies reported the opposed findings; presence of hemodynamic turbulence has little to do with the location of VF defects42, and no significant differences were found between NTG and high tension glaucoma regarding the slopes or depths of the VF defect43. Moreover, no difference in systemic and vascular factors between patients with paracentral and peripheral VF defects was found45. Park et al.46 found totally overturned results that eyes with paracentral VFD had distinctive ocular and systemic hemodynamic features. In spite of existence of controversy over the relationship between hemodynamic factors and paracentral VF defect progression, based on our findings, the dominance of paracentral VF defect in the DVD group might imply that damages in choroidal microcirculation contribute to the development of glaucoma ahead of the presence of the glaucomatous changes in the superficial layer.Furthermore, we examined the location of the VF defects, and for the DVD group, the prevalence of the paracentral VF defect was significantly higher, compared to the SVD group. Relevance between vascular incompetence and paracentral VF defect in NTG has been analyzed. Specifically, one preceding study suggested that NTG patients with paracentral scotoma were likely to have nocturnal dip and large blood pressure variability48. Last, we confined the patients’ pool to early stage of glaucoma. Though it was our aim to examine changes in the inchoate disease, further study may be needed with diverse stage and relatively large number of patients.Our study has several limitations. Firstly, OCTA is a relatively latest implement, compared to OCT. Therefore, it was unavoidable to extract baseline data of OCT and OCTA from different time points. Secondly, there are issues regarding OCTA imaging interpretation, particularly in deep layer. Namely, retinal vessel signals evident on en face, and this hinders researchers to examine deep layer precisely. Nevertheless, recent studies have found that repeatability and reproducibility in measurement were good in superficial layer as well as in deep layerIn conclusion, in early NTG, various disease parameters showed the distinctive correlations to the respective vascular layer. In other words, the factors showing disease severity, such as average GCIPLT, PSD, were correlated with the width of the superficial VD, while IOP, CCT, and age were significant determinants in the width of the deep VD. Also, the higher frequency of paracentral VF defects in the DVD group was noticeable. Through these findings, vascular circulation not only in superficial layer but also in deep layer would be considered in normal-tension glaucoma patient’s evaluation and management.This study was conducted in a retrospective, observational design, and was approved by the Institutional Review and Ethics Boards (IRB) of Seoul St. Mary’s Hospital, South Korea. (KC20RISI0849). The study also followed all relevant tenets of the Declaration of Helsinki. Informed consent was waived due to the characteristics of retrospective study’s design. The waiver was approved by the IRB of Seoul St. Mary’s Hospital, South Korea who has waived the need of informed consent for this study.We collected patient data from July 2011 to July 2020 using the electronic medical record and those patients were referred to the glaucoma clinic at Seoul St. Mary’s Hospital for glaucoma screening. Each participant underwent a comprehensive ophthalmic assessment, including the measurement of best-corrected visual acuity (BCVA), refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, central corneal thickness using ultrasound pachymetry , the determination of axial length (AL) using ocular biometry , dilated stereoscopic examination of the optic disc and fundus, color disc photography, red-free RNFL photography , optical coherence tomography (OCT), and Humphrey VF examination  at initial work-up. After the initial visit, the patients were followed-up to the clinic every 6 to 12 months according to their disease severity. Since OCTA  examinations were available from March 1, 2016, all patient could undergo these tests after that point.Regarding IOP, we set two parameters to analyze their relationship with variables: baseline IOP, which was measured at the first visit of the clinic, and treated IOP was accessed at the last visit regardless of use of glaucoma medication.49, and presence of a discrete localized RNFL defect either on RNFL photograph or on OCT, OCTA images quality scores greater than 60.The inclusion criteria were: a BCVA of ≥ 20/40, IOP under 21 mmHg, a mean deviation (MD) better than − 6.00 decibels (dB) based on the Hodapp-Anderson-Parish criteriaP < 5%, or a Glaucoma Hemifield Test result outside the normal limits in a consistent pattern on two qualifying VFs), confirmed by two glaucoma specialists (H.Y.-L.P. and C.K.P.); and an open-angle on gonioscopy50.Normal tension glaucoma (NTG) diagnosis was defined by glaucomatous optic disc appearances ; IOP of less than 21 mmHg at least two different visits; VF consistent with glaucoma ; a history of any retinal disease, including diabetic or hypertensive retinopathy or other retinal complications; a history of eye trauma or surgery, including glaucoma incisional surgery or laser treatment; or a history of systemic or neurological diseases possible to affect the VF. If both eyes were eligible, one eye was randomly selected from each patient.The microvasculature of the peripapillary area was imaged via swept- source OCTA device , which uses a laser with a wavelength of 1050 nm and scan speed of 100,000 A scans per second. The OCTA provided en face images through automated layer segmentation around the optic nerve head into 4 layers. Among those, we chose the radial peripapillary capillary (RPC) mode, which estimate a 70 µm thick layer below the internal limiting membrane (ILM), to assess the superficial layer. As for the deep layer, the original choroidal/disc mode was customized for the measurement. Namely, it was intended to measure from 130 µm below the ILM to 390 µm below Bruch’s membrane, however, we manually reset the starting point as 0 µm below inner plexiform layer/inner nucleus layer (IPL/INL) to exclude the changes of the superficial layer.Images with quality score less than 50 and unclear ocular vascular structures were excluded for further analysis.http://rsb.info.nih.gov/ij/index.html; developed by Wayne Rasband, National Institutes of Health, Bethesda, MD, USA) was adopted. At the edge of the optic disc, the point where the border of the localized VD met with the edge was identified, then straight lines were drawn to the center of the optic disc, respectively. The angle which was generated between two lines was measured, and was defined as the width of the VD  group, and the other with wider deep VD (DVD) group. The significant difference between the widths of the VD in each layer was defined as the width variation greater than 10 degree in two layers. Accordingly, if the width of the superficial layer was 10 degree wider than that of the deep layer, the patient was allocated to the SVD group, and vice versa.Patients were classified as being present or absent of paracentral VF defect, which was defined by presence of one or more significant points in the central 10° with a probability of less than 0.5% on the pattern deviation map.P value of less than 0.05 was considered statistically significant. Correlation coefficients were calculated to evaluate the relationship between the width of the VD in each layer and ocular or clinical parameters by Pearson correlation analysis. Linear regression analysis was applied to explore meaningful factors affecting the width of the VD. The variables with significance at P < 0.10 in univariate analysis were included in the multivariate model. P < 0.05 was considered to represent statistical significance.All statistical analyses were performed using the SPSS statistical package  and student’s t-test were adopted to compare the differences between the groups. The chi-square test or Fisher’s exact test was applied to compare frequencies. A


In the interaction analysis, normal blood gas phenotype  × TTI ≦ 6.3 min  and non-severe acidosis × TTI ≦ 6.3 min  were associated with neurological recovery while metabolic acidosis × TTI ≦ 5.7 min  and hypercapnic acidosis × TTI ≦ 10.4 min  were associated with survival. Intra-arrest blood gas analysis may help guide TTI during for patients with IHCA.To investigate whether the optimal time to tracheal intubation (TTI) during cardiopulmonary resuscitation would differ by different blood gas phenotypes. Adult patients experiencing in-hospital cardiac arrest (IHCA) from 2006 to 2015 were retrospectively screened. Early intra-arrest blood gas analysis, performed within 10 min of resuscitation, was used to define different phenotypes. In total, 567 patients were included. Non-severe acidosis (pH≧7.15) was associated with favourable neurological outcome (odds ratio [OR]: 4.60, 95% confidence interval [CI] 1.63–12.95;  Twenty-four percent of patients with IHCA survive to hospital discharge; among these patients, 14% sustain significant neurological disability1.Approximately 209,000 patients experience in-hospital cardiac arrest (IHCA) in the United States annually2. However, clinical data on point-of-care blood gas analysis during CPR are limited.When treating cardiac arrest, point-of-care blood testing may yield important diagnostic information and guide therapeutic management during cardiopulmonary resuscitation (CPR). For example, the diagnosis of hyperkalaemia could enable the clinicians to rapidly administer potassium-reducing agents to reverse this life-threatening electrolyte abnormality during CPR3. Thus, substantial heterogeneity exists between patients even if they are classified within the same category. In scenarios such as prehospital CPR, this crude classification system may be necessary; nonetheless, for IHCA resuscitation, a more elaborate categorization may facilitate the application of appropriate therapeutics. For example, studies5 indicated that tracheal intubation during CPR may cause harm for patients without respiratory failure prior to IHCA but may not do so for patients with prior respiratory failure.For epidemiological and research purposes, aetiologies of out-of-hospital cardiac arrest are usually categorised into medical and non-medical causes based solely on contextual data without the incorporation of diagnostic testingIn this study, we first attempted to investigate whether intra-arrest blood gas analysis could help classify IHCA patients into distinct phenotypes with different prognoses; second, we attempted to investigate whether the optimal timing of tracheal intubation would differ according to different phenotypes. Besides traditionally defined blood gas phenotypes, we would also attempt to identify new phenotypes which may influence the optimal timing of tracheal intubation.7. Briefly, the patient data were collected retrospectively at the National Taiwan University Hospital (NTUH). As a tertiary medical centre, NTUH has 2600 beds, including 220 beds in intensive care units (ICUs). This study was performed in accordance with the Declaration of Helsinki amendments. The NTUH Research Ethics Committee approved this study (reference number: 201805098RINC) and waived the requirement for informed consent because of the retrospective and non-interventional nature. In NTUH, a code team is activated whenever an IHCA event occurs in the general wards. A code team consists of a senior resident, several junior residents, a respiratory therapist, a head nurse and several ICU nurses. For IHCA occurring in the ICUs, CPR is performed by the ICU staff without activating a code team. Resuscitation was performed according to recommendations of CPR guidelines9. In NTUH, point-of-care blood gas analysers were deployed in every ward floor, including floor of general wards and ICUs. Physicians were instructed to obtain blood samples as soon as possible for blood gas analysis in order to identify potential causes leading to IHCA. There were no supra-glottic airways available for IHCA resuscitation in NTUH.We used previously established IHCA database for analysis2), and bicarbonate (HCO3-) level data and (5) tracheal intubation during CPR. Tracheal intubation included endotracheal intubation, tracheostomy and cricothyroidotomy. If a single patient experienced IHCA events more than once during the hospitalisation, only the first event was analysed. Trauma-related arrest was excluded. The number of patients fulfilling the above criteria during the study period determined the sample size.Patients experiencing IHCA at NTUH between 2006 and 2015 were screened. Patients fulfilling the following criteria were included for analysis: (1) age above 18 years, (2) chest compressions performed for ≥ 2 min, (3) absence of a do-not-resuscitate order before CPR, (4) early intra-arrest blood gas analysis with available blood pH, partial pressure of carbon dioxide . Sustained ROSC was defined as ROSC lasting consecutively for at least 20 min. Time to intubation was defined as the time interval between the initiation of chest compression to the completion of tracheal intubation. Duration of CPR was recorded as the time interval between the initiation of chest compression until termination of CPR, either due to sustained ROSC or due to declaration of death.The following information was extracted for each patient: age, sex, comorbidities, variables recommended by the Utstein template2 and HCO3- were measured using point-of-care blood gas analysers. Patients were classified into 5 traditionally defined blood gas phenotypes based on a combination of pH, PCO2 and HCO3− levels12: (1) normal , (2) non-acidosis, except normal , (3) hypercapnic acidosis , (4) metabolic acidosis , (5) mixed acidosis .Early intra-arrest blood gas analysis was defined as the first available blood gas data measured within 10 min of initiating CPR, which was usually obtained in the beginning of CPR. The sample for blood gas analysis could be obtained from arterial or venous sources, which could not be verified retrospectively. Blood pH, PCO13. Survival at hospital discharge was selected as the secondary outcome.Favourable neurological status at hospital discharge was selected as the primary outcome, which was defined as one or two points on the Cerebral Performance Category scalep value < 0.05 was considered significant.We used R 3.3.1 software  to analyse data. Categorical variables are presented as counts with proportions, and continuous variables are presented as medians with interquartile ranges. Categorical variables were examined by Chi-squared test while continuous variables were compared by Wilcoxon’s rank-sum test. A two-tailed 14 to explore non-linear effects of all continuous variables on outcomes and to identify the optimal cut-off points to transform these continuous variables into binary ones, which would also be tested in the regression analyses. Furthermore, the cut-off points identified for pH, PCO2 and HCO3- would be used to define new phenotypes. Because the blood gas analysis data, including pH, PCO2 and HCO3-, were used to define different phenotypes, they were not included as independent variables during the model-fitting process. We developed the final regression model by stepwise variable selection procedure with iterations between the forward and backward steps. We defined the significance levels for entry and to stay at 0.15 to avoid exclusion of potential variables. We determined the final regression model by excluding non-significant variables sequentially until all regression coefficients were significant.We calculated the odds ratio (OR) as the outcome measure. We conducted univariate and multivariable logistic regression analyses to investigate the associations between variables of interest and outcomes. We placed all available independent variables in the regression model for selection, irrespective of whether they were considered as significant in univariate analyses. We employed generalised additive models (GAMs)c statistics, the adjusted generalised R2 and the Hosmer–Lemeshow goodness-of-fit test.In the primary or secondary model, the multivariable analysis was intended to identify the phenotypes associated with primary or secondary outcome, respectively. In the interaction analysis, the interaction between each phenotype and time to intubation was assessed during the model-fitting process. We assessed the goodness-of-fit of the regression models by We performed a sensitivity analysis to assess the influence of patients with missing blood gas analysis data. We performed the multiple imputation procedure to impute the missing data. The packages of Amelia and Zelig were employed. We used predictors altogether to impute the missing values. Ten datasets were imputed, and each dataset was used individually to fit the final regression model obtained in the primary analysis. The ten fitted results were then pooled into a single coefficient in the regression model.As shown in Supplemental Figure 2, and HCO3− levels were 7.2, 54.3 mmHg and 19.6 mmol/L, respectively. Hypercapnic acidosis was the most dominant traditional blood gas phenotypes . Only 66 patients (11.6%) survived to hospital discharge; of these, 30 patients (5.3%) demonstrated favourable neurological status.The features of included patients are presented in Tables 2, and HCO3− levels, respectively  non-severe acidosis (pH ≧ 7.15), (2) severe hypercapnic acidosis , (3) severe metabolic acidosis , (4) severe mixed acidosis . Both the new and traditional blood gas phenotypes were placed in the variable list for variable selection during the process of building primary and secondary models. Similarly, time to intubation was transformed into a binary variable based on GAM plots , where p represented the probability for the primary outcome, with pH, PCOely Fig. . If logi pH ≧ 7.1, (2) sevp value = 0.004). The baseline characteristics and IHCA features stratified by severe acidosis are presented in Supplemental Tables p value = 0.005) and non-severe acidosis × time to intubation ≦ 6.3 min  were positively associated with favourable neurological outcome.For the primary outcome Table , in the p value < 0.001). In the interaction analysis, both metabolic acidosis × time to intubation  ≦  5.7 min  and hypercapnic acidosis × time to intubation  ≦  10.4 min  were positively associated with survival.For the secondary outcome Table , in the In the sensitivity analysis, we imputed the data for the 26 patients who had missing blood gas analysis data and were excluded from the primary analysis. As shown in Supplemental Table The results suggest that intra-arrest blood gas analysis might be used to classify IHCA patients into distinct phenotypes with different prognoses and responses to intervention. Non-severe acidosis, one of the phenotypes, was found to be positively associated with better neurological and survival outcomes. In the interaction analysis, for patients with non-severe acidosis, shorter time to intubation was associated with favourable neurological outcome, while for patients with metabolic or hypercapnic acidosis, shorter time to intubation was associated with improved survival. The results of interaction analysis suggested that the effects of time to intubation may differ between different phenotypes. Phenotyping by blood gas analysis may enable patient-tailored intervention during CPR.9, which significantly influences outcomes and necessitates prompt defibrillation for the former. However, beyond this, there are few reported features able to phenotype patients and essentially, all patients receive universal or one-size-fits-all managements9. The inability to phenotype patients may weaken the benefits of a certain intervention in some subgroups, or even cause harm, which might explain the abundant neutral results from clinical trials on cardiac arrest15. Point-of-care blood gas analysis had the potential to phenotype patients during CPR and guide corresponding treatment. Our results demonstrated a significant benefit of shorter time to intubation for patients with non-severe acidosis and normal blood gas phenotype regarding favourable neurological recovery. The normal blood gas phenotype was actually a subgroup of non-severe acidosis. Because the effects of shorter time to intubation were substantially greater for normal blood gas phenotype than non-severe acidosis (OR: 20.40 versus 3.35), the variables of shorter time to intubation with respective phenotypes were present in the primary model with interaction terms simultaneously. Earlier intubation during CPR may facilitate better control of ventilation and oxygenation16, resulting in better outcomes.The most common feature used to phenotype patients during CPR may be the initial arrest rhythm, i.e. shockable versus non-shockable rhythm17 once reported that as high as 98% of OHCA patients had intra-arrest pH < 7.35. The mix of patients with high or low “resuscitability” may have thus nullified the potential benefits of intubation on long-term neurological and survival outcomes in previous studies18. In contrast to OHCA resuscitated in the out-of-hospital environment, IHCA patients usually could be attended earlier with more healthcare personnel involved. Therefore, it may be more likely for in-hospital code teams to conduct point-of-care blood gas analysis in determining whether early tracheal intubation should be performed during CPR for IHCA patients.In our study, the benefits of shorter time to intubation were only observed in patients of non-severe acidosis, suggesting that the tracheal intubation may only be effective for patients with higher “resuscitability,” i.e. patients with higher chances of achieving favourable neurological or survival outcomes. Spindelboeck et al19 used large registry data to investigate the effect of tracheal intubation. Despite the increased statistical power with the larger study population19, the patients could only be classified under broad medical categories, such as shockable or non-shockable rhythm. In contrast, the phenotypes classified by blood gas analysis might be more reflective of the real-time pathophysiological states and be more appropriate to guide the corresponding treatment. The confounding effects of the different blood gas phenotypes, such as non-severe acidosis, could not accounted for in these studies19, which might lead to the heterogeneous results.Most studies22, PCO223, base excess24, and lactate25 levels, were used as single prognosticators to predict outcomes following CPR. For clinicians, it may be difficult to remember these individually identified predictors and relevant cut-off points in predicting poor outcomes. The use of common phenotypes, such as hypercapnic or metabolic acidosis, may be more familiar and intuitive for clinicians to react with corresponding interventions.Because our study was based on a highly selected cohort , the results should be further examined before clinical use. For example, the blood pH value used to define severe acidosis may need more patients to be validated. However, in the secondary model, we did find that for patients with traditionally defined hypercapnic or metabolic acidosis, shorter time to intubation was associated with better survival, which may be more clinically relevant. In most previous studies, point-of-care intra-arrest blood gas analysis data, such as pH27, discrepancies between arterial and venous PCO2 levels have been reported28. This could only be resolved by a prospective study adopting a certified method to obtain arterial blood gas. Third, we did not record the timing and the amount of sodium bicarbonate administered during CPR. The changes in blood pH, PCO2 or HCO3- caused by administration of sodium bicarbonate29 may lead to misclassification bias, which may nullify the association between some blood gas phenotypes and outcomes. However, since the administration of sodium bicarbonate may not significantly improve or worsen the resuscitation outcomes29, the effect of misclassification bias could probably be mitigated to some extent. For example, the significant association between non-severe acidosis and neurological outcomes was still identified in the regression analysis. Fourth, despite that we had accounted for the confounding effects of CPR duration and time to intubation, the resuscitation time bias30 may still be concerning since those patients without intubation during CPR were excluded from the analysis. Fifth, the exact timing of obtaining blood gas samples was not recorded in the previously established IHCA database7 and therefore, we could not verify whether the timing of obtaining blood gas samples was prior to the timing of intubation or administration of sodium bicarbonate. Nonetheless, since the clinicians in NTUH were instructed to obtain blood gas analysis as soon as possible in the beginning of CPR, the interval between the timing of blood gas analysis and intubation or administration of sodium bicarbonate may be quite small (maximum: 10 min), which may not cause significant changes in blood gas analysis data. Finally, during the study period between 2006 and 2015, the guidelines32 did not recommend the optimal timing of tracheal intubation. The timing of tracheal intubation might be influenced by other unmeasured confounders, such as clinicians’ experience in tracheal intubation. While early tracheal intubation was associated with better outcomes in some phenotypes, the generalizability of this practice should be further examined in a prospective study since this study was based on a highly selected cohort. What was emphasized in the current study was that blood gas analysis could help classify patients into different phenotypes that were associated with outcome and with the effect of a certain intervention. However, the phenotypes may be simplified, and the cut-off points used may not be accurate. Therefore, results of the current investigation are best viewed as a proof-of-concept rather than a definite conclusion, which should be further examined in a prospective study.First, because of the nature of a retrospective study design, we could only establish an association, rather than a causal relationship, between independent variables and outcomes. Additionally, the effects of unmeasured confounding factors may also introduce bias into the analysis. For example, the indications for blood gas analysis and tracheal intubation could not be retrospectively obtained and adjusted for in the multivariable analysis. Second, blood sampling during CPR was technically difficult and therefore, it was difficult to verify whether blood sample was drawn from an artery or a vein source. Although venous pH may be consistent with arterial pHIntra-arrest blood gas analysis may assist in phenotyping patients with IHCA. Non-severe acidosis was associated with better neurological and survival outcomes. For patients with non-severe acidosis, early tracheal intubation was associated with favourable neurological outcome, while for patients with metabolic or hypercapnic acidosis, early tracheal intubation was associated with improved survival.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Supplementary Information 5.Supplementary Information 6.Supplementary Information 7.Supplementary Information 8.Supplementary Information 9.Supplementary Information 10.Supplementary Information 11.Supplementary Information 12.Supplementary Information 13.


EGFR (p = 0.001) was the strongest potentially modifiable predictor of a complication. Predictor-adjusted risks of blood transfusions and acute postoperative complications were calculated for Hb and eGFR. Hb = 12.5 g/dL, BMI = 17.6 kg/m2, and eGFR = 54 min/mL were associated, respectively, with a 10% risk of a blood transfusion, eGFR = 59 mL/min was associated with a 10% risk of a complication. Conclusion: The individual risks for blood transfusions and acute postoperative complications are strongly increased in patients with a low preoperative Hb, low BMI or low eGFR. We recommend aiming at a preoperative Hb ≥ 13g/dL, an eGFR ≥ 60 mL/min and to avoid a low BMI. Future studies must show if a preoperative increase of eGFR and BMI is feasible and truly beneficial.Background: The primary aim of this study was to identify modifiable patient-related predictors of blood transfusions and perioperative complications in total hip and knee arthroplasty. Individual predictor-adjusted risks can be used to define preoperative treatment thresholds. Methods: We performed this retrospective monocentric study in orthopaedic patients who underwent primary total knee or hip arthroplasty. Multivariate logistic regression models were used to assess the predictive value of patient-related characteristics. Predictor-adjusted individual risks of blood transfusions and the occurrence of any perioperative adverse event were calculated for potentially modifiable risk factors. Results: 3754 patients were included in this study. The overall blood transfusion and complication rates were 4.8% and 6.4%, respectively. Haemoglobin concentration (Hb,  The probabilities of blood transfusions and perioperative complications in total joint arthroplasty (TJA) are highly influenced by patient-related risk factors such as age and comorbidities ,2. To loA frequently reported modifiable risk factor is a low preoperative haemoglobin (Hb) concentration, which is not only associated with a higher rate of blood transfusions but also renal, cardiac and wound-related complications . Since aTherefore, we performed this study to investigate the predictive value of the preoperative Hb concentration and other patient-related risk-factors for blood transfusions and acute postoperative complications. On the basis of this data, we aimed to define useful target values of a preoperative treatment.We performed this monocentric retrospective study after approval of the local ethics committee  and completed registration at the German register for clinical studies .We collected the data of all patients that underwent elective total hip and bicondylar knee arthroplasty between January 2016 and December 2018 in a single orthopaedic university hospital.3/µL), creatinine (µmol/L), estimated glomerular filtration rate (eGFR) (mL/min) Quick (%) and partial thromboplastin time (PTT) (sec).Demographic, anamnestic and clinical data were collected retrospectively from the hospital’s information technology system . Data about the use of allogeneic and autologous blood transfusions were crosschecked using hard copy records. Of the demographic and anamnestic data, we recorded the patient’s age, sex, height and weight as well as the preoperative medication, daily consumption of alcohol or nicotine and comorbidities. Of the preoperative clinical data, we recorded the American Society of Anaesthesiologists (ASA) status and the lab values of the last blood sample before undergoing surgery, including c-reactive protein (mg/dL), haemoglobin concentration (g/dL), haematocrite (%), mean corpuscular volume (MCV) (fl), platelet count . The administration of at least one allogeneic red blood cell (RBC) transfusion was the primary outcome of this investigation. According to the hospital’s guideline, an Hb concentration <6 g/dL was an unconditional trigger for RBC transfusions. A Hb concentration <8 g/dL was a conditional trigger regarding the patient’s individual resources and clinical symptoms. Blood transfusions in patients with a Hb concentration >8 g/dL were well-founded exceptions.The secondary outcome measure was the occurrence of an adverse event during the patient’s stay in hospital that required an unexpected change of treatment. Statistical analysis was performed on deidentified data using SPSS Statistics 26 .p ≤ 0.01. Variables were removed from the model, when adding of further variables reduced the significance of the variable dependent improvement to p ≥ 0.05.To investigate the predictive power of the preoperative characteristics, we calculated logistic regression models for both outcome measures. To include only the strongest predictors, we modified the inclusion and exclusion criteria for the regression models. To predict an allogeneic RBC transfusion, a variable was included in the model when its inclusion improved the model fit with a significance of p ≤ 0.05. Variables were removed from the model when adding of further variables reduced the significance of the variable dependent improvement to p ≥ 0.1.To predict a complication, a variable was included in the model when its inclusion improved the model fit with a significance of In case the logistic regression models revealed a potentially modifiable risk factor for the outcome measures, we calculated a monovariate logistic regression model for the respective risk factor to receive a continuous estimation of the predictor-adjusted risks. 2. The mean ASA score (IQR) was 2 (2–3). The most common comorbidities were high blood pressure (63.9%), cardiovascular disease (22.2%), hypothyreosis (17.6%) and pulmonary disease (17.3%). The mean (±SD) preoperative haemoglobin (Hb) concentration was 14.1 (±1.4) g/dL and the mean (±SD) estimated glomerular filtration rate (eGFR) was 84.5 (±21.2) mL/min. Further comorbidities and preoperative lab values are shown in We analyzed the data of 2109 female and 1645 male patients who underwent total joint arthroplasty. The mean age  was 66.5 (±11.1) years, the mean body mass index (±SD) was 29.5(±5.8) kg/mA total of 1806 patients underwent primary bicondylar arthroplasty via the medial parapatellar approach and 1948 patients underwent primary total hip arthroplasty via the direct anterior approach according to Hueter [Allogeneic red blood cell (RBC) transfusions were applied in 179 (4.8%) patients. Adverse events during the patient’s stay in hospital were recorded in 239 (6.4%) patients.p < 0.001), cardiovascular disease (p < 0.001), low body mass index (p < 0.001), diabetes (p = 0.001), ASA score (p = 0.001), haemophilia (p = 0.002), thrombocytes (p = 0.003), estimated glomerular filtration rate  and age (p = 0.027) were the strongest predictors. In the multivariate logistic regression model for a perioperative complication the ASA status (p < 0.001), age (p < 0.001), eGFR (p = 0.001) and Quick (0.002) were the strongest predictors  [2, respectively.To estimate the risks of blood transfusions in a cohort of high-risk patients with a low Hb concentration (Hb < 13 g/dL), low BMI (<22 kg/m2)  or a lowFor acute postoperative complications, the OR (95% CI) was 2.75 (2–3.78) in patients with eGFR < 60 mL/min. Within the recorded kinds of complications, the OR (95% CI) was significantly increased for cardiac complications (2.45 (1.27–4.7)), falls (3.37 (1.18–9.61)) and renal complications (8.84 (5.16–15.16)) .This study was performed to investigate potentially modifiable patient-related risk factors for blood transfusions and acute postoperative complications in total joint arthroplasty. Our results show that numerous patient-related characteristics are potential risk factors for blood transfusion . Some ofIn our study, we focused on potentially modifiable predictors of blood transfusions such as a low body mass index (BMI), a low estimated glomerular filtration rate (eGFR) and a low haemoglobin (Hb) concentration. Our results confirm the results of a previous study that a high body mass index is a protective factor for blood transfusions in major surgery . Since aIn contrast, a low Hb concentration is a highly predictive factor of a blood transfusion that can also be addressed by a short-term preoperative treatment  using irAlthough in our study the overall rate of transfusions was under 5%, our results showed that many patients undergo a much higher individual probability of a blood transfusion. For instance, if the Hb concentration was 12.5 g/dL or less, the individual transfusion risk exceeded 10% . In our Another finding of our study showed that the preoperative estimated glomerular filtration rate (eGFR) was a predictive factor of blood transfusions as well, which has been reported before ,23. Poss2) and eGFR (60 mL/min) thresholds, we created “high-risk” groups to illustrate the impact on the transfusion rate , BMI  is also a significant risk factor for blood transfusions but also for acute postoperative complications. Patients with an eGFR under 60 mL/min had a five-fold higher risk of transfusions and three-fold higher risk of complications. Future studies must show if it is possible to increase the eGFR in the run-up for total joint arthroplasty and if the transfusion and complication rates can be further reduced.The third modifiable risk factor for blood transfusions was a low BMI. Therefore, malnutrition should also be addressed during “prehabilitation” for total joint arthroplasty.


Hypertension is a known risk factor for several chronic conditions including diabetes and cardiovascular diseases. However, little is known about its impact on Health-related quality of life (HRQoL) in the context of Bangladesh. This study aimed to evaluate the association of hypertension on HRQoL among Bangladeshi patients corresponding to the socio-demographic condition, comorbid conditions, treatment, and health outcomes.A hospital based cross-sectional study was conducted using a pre-tested structured questionnaire among patients with hypertension in 22 tertiary medical college hospitals in Bangladesh. The study recruited male and female hypertensive patients of age ≥18 years between July 2020 to February 2021 using consecutive sampling methods. Health related quality of life was measured using the widely-used index of EQ-5D that considers 243 different health-related attributes and uses a scale in which 0 indicates a health state equivalent to death and 1 indicates perfect health status. The five dimensions of the quality index included mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Ordered logit regression and linear regression models were used to estimate the predictors of comorbidity and HRQoL.Of the 1,912 hypertensive patients, 56.2% were female, 86.5% were married, 70.7% were either overweight or obese, 67.6% had a family history of hypertension, and 85.5% were on anti-hypertensive medication. Among the individuals with comorbidities, 47.6% had diabetes, 32.3% were obese, 16.2% had heart disease, 15% were visually impaired, and 13.8% were suffering from psychological diseases. HRQoL was found to be inversely proportional to the number of comorbidities. The most frequent comorbidities of diabetes and obesity showed the highest EQ- 5D mean utilities of 0.59 and 0.64, respectively.Prevalent comorbidities, diabetes and obesity were found to be the significant underlying causes of declining HRQoL. It is recommended that the comorbidities should be adequately addressed for better HRQoL. Special attention should be given to address mental health issues of patients with hypertension.The online version contains supplementary material available at 10.1186/s12889-022-12562-w. With increasing life expectancy and a rise in the aging population, a large number of people are currently living with various chronic diseases worldwide which grossly impairs their Health Related Quality of Life (HRQoL) . HyperteHealth-related quality of life (HRQoL) is a multidimensional archetype, which contains five broad domains: resilience, health perception, functional states, impairment/diseases, and duration of life that altogether denotes the concordance between how long and how well an individual might live . HRQoL aPreviously only a few studies have explored the association between HRQoL and hypertension globally. Among them, a study conducted among the US Hispanic people reported lower HRQoL among the hypertensive patients . HRQoL oAlthough some previous studies have evaluated HRQoL among patients of type-2 Diabetes Mellitus in Bangladesh –17, simiThe objective of this study is two-fold. First, it examined the relationship between hypertension and HRQoL among patients with hypertension taking socio-demographic factors and comorbidities under consideration. Second, it explored the role of comorbidities such as diabetes, chronic obstructive pulmonary disease (COPD), obesity and anxiety/depression on the HRQoL of people with hypertension.This cross-sectional study was carried out among patients with hypertension attending 22 tertiary medical college hospitals of Bangladesh between July 2020 and February 2021. All of these hospitals combinedly provide treatment for around 20 million residents in major cities and adjacent districts. Both men and women aged above 18 years old were included in this study. All the participants were confirmed to have hypertension, diagnosed by medical professionals as defined per WHO criteria of persistent systolic blood pressure (SBP) of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg . BesidesA structured pilot-tested questionnaire was used for data collection. Face-to-face interviews were conducted by trained and qualified data collectors of both male and female sex. The study’s principal investigator and co-principal investigators strictly monitored data collection phases to ensure work efficiency and quality of collected data were maintained. The questionnaire asked for information related to age, sex, education, occupation, monthly income, duration of hypertension, family history of hypertension, and medication. Interviews were conducted in a secure place in the hospitals maintaining privacy after obtaining written consent of the participants.A structured, eight-item EQ-5D-3L tool was adapted to assess the HRQoL of the participants. The HRQoL records were self-reported and the tool was previously validated in different study settings prior to conduction of interviews . The EQ-The study used the independent variables, mostly categorical, representing different socio-demographic characteristics. Ages were categorized as “18-29”, “30-39”, “40-49”, “50-59”, and “60 and above”, and the educational attainment of the respondents were categorized as “Not educated”, “Primary school”, “Secondary school”, “Higher secondary”, and “Bachelor and above”. Marital status was recorded with three levels namely “Married”, “Unmarried”, and “Separated or widowed” and employment status with “Not employed” and “Employed”. The total family income of individuals were categorized as “Less than USD238”, “USD238-<USD417”, “USD417-<USD595”, “USD595-< USD893”, “USD893-< USD1,190”, and “≥ USD1,190”. Information on gender and residence were also collected. The study included two dichotomous variables, family history of hypertension and medication use. Self-reported comorbidities entered different models as count variables. Anthropometric measurements of weight, height, were measured using standardized protocols and calibrated equipment and used for calculation of BMI. Systolic and diastolic blood pressures (BP) were measured twice using digital BP machines  at 10-minutes intervals and the averages of the two readings were used for this analysis. In addition to collecting systolic and diastolic BP data, other co-morbidities were recorded from the self-report during interviews, which were further confirmed by reviewing each participant’s medical records.Comorbidity data were determined by self-reports by the participants initially through yes/no responses to the questions implying “Has a doctor ever diagnosed that you had...”. The trained interviewer also verified the reported chronic illnesses through checking previous medical records of the patients, and laboratory diagnosis reports as well as the medications list of the participants to ensure the accuracy and comprehensiveness of the data.This study was approved by the Ethical Review Committee of Chittagong Medical College Hospital (CMC/PG/2020/27). Written informed consent, before the interview, was obtained from all participants. The objectives and procedures of the study were explained to the participants in their native language .A total of 1,963 hypertensive individuals were approached, of whom 1,912 respondents completed the full survey and thus constitute the final study sample. Descriptive analyses were carried out by comorbid and non-comorbid groups, where the comorbid group included participants who reported having at least one chronic condition. Those reporting no chronic morbidity other than hypertension constituted the non-comorbid group. Continuous variables were analyzed as means and standard deviations and the categorical variables as frequencies and proportions along with presenting 95% confidence intervals and chi-squared test. The two continuous variables named systolic BP and diastolic BP were found to be normally distributed. No specific model selection techniques were used in finalizing the equations of interest as followed by Zhang L et al (2017) and Zhang Y et al (2016). An ordered logit regression model was estimated for each of the five problem dimensions of EQ-5D measure namely mobility, self-care, usual activity, pain, and anxiety/depression. Ordered logit regression model was used because of the inherent ordering of the health dimension states that include “no problem”, “some problem”, and “extreme problem”. Finally, multiple linear regression models were used to estimate the ceteris paribus impact of comorbidity on HRQoL of hypertensive patients. For the robustness check, a simple linear regression model, with comorbidity as the only independent variable, was estimated. Then, the stability of the regression estimates was tested by step-wise addition of the socio-demographic variables and the health-related variables. The Variance Inflation Factors (VIFs) were calculated to check if multicollinearity exists in the data. All VIFs were found to be smaller than 10, indicating that multicollinearity may not be a problem. No specific model selection techniques were used in finalizing the equations of interest as followed by Zhang et al 2017 and Zhang et al 2016 , 25. STA2 and obese (27.1%) (Table The respondents of this study belonged to the 18 – 98 years age group. The median age of the respondents was found to be 52 years. About one-third (33.3%) of the respondents were between 50 and 59 years old, and 56.2% were female  reported having suffered from at least one chronic condition . Among the respondents, 36.2% had single comorbidity, 18% had two, 7.5% had three, and 3.4% had four or more comorbid conditions. Males were found to have more comorbid conditions, showing higher percentages in all types of comorbidities, compared with females . Respondents with comorbidity were found to have more likelihood of reporting poor health quality than patients with no comorbidities (12.9% vs. 4.3%) , followed by obesity in nearly one-third of the patients with hypertension. Obesity and diabetes were also found to be the main contributors to poor HRQoL among patients with hypertension in Italy and Japan. It was reported widely that presence of metabolic syndrome including diabetes mellitus, obesity and hypertension had a negative influence on HRQoL in various populations , 28. HowAll the five health quality indicators such as mobility, self-care, usual activity, pain/discomfort, and anxiety/depression were found to be higher among hypertensive patients with comorbidities than the non-comorbid participants  and HRQoL.Additional file 1: Table 1. Prevalence of the problems considered in the HRQoL measure by comorbidity status.