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Abstract
In persistent pulmonary hypertension of the newborn (PPHN), the ratio of pulmonary vascular resistance to systemic vascular resistance is increased. Extrapulmonary shunts (patent ductus arteriosus and patent foramen value) allow for right-to-left shunting and hypoxaemia. Systemic hypotension can occur in newborns with PPHN due to variety of reasons, such as enhanced peripheral vasodilation, impaired left ventricular function and decreased preload. Systemic hypotension can lead to end organ injury from poor perfusion and hypoxaemia in the newborn with PPHN. Thus, it must be managed swiftly. However, not all newborns with PPHN and systemic hypotension can be managed the same way. Individualised approach based on physiology and echocardiographic findings are necessary to improve perfusion to essential organs. Here we present a review of the physiology and mechanisms of systemic hypotension in PPHN, which can then guide treatment.
- cardiology
- neonatology
Data availability statement
No data are available. A review article with no data.
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Introduction
The fetal circulatory system is characterised by high pulmonary vascular resistance (PVR) and low systemic vascular resistance (SVR). The high PVR is due to relative hypoxaemia, lack of alveolar ventilation with fluid-filled lungs and circulating pulmonary vasoconstrictors.1 The low SVR is secondary to low-resistance umbilical and placental circuit. High PVR and low SVR lead to right-to-left shunts at the level of the patent ductus arteriosus (PDA) and patent foramen ovale (PFO). At birth, alveolar ventilation and oxygenation reduces PVR with an 8-fold to 10-fold increase in pulmonary blood flow, and cord clamping increases SVR. The high SVR and low PVR with a systemic blood pressure significantly higher than pulmonary arterial pressure is a lifelong feature of postnatal circulation unless altered by disease. Failure to achieve this transition leads to persistence of high PVR in the postnatal period, leading to persistent pulmonary hypertension of the newborn (PPHN).2 This review outlines the aetiology and management of systemic hypotension in PPHN.
Pathophysiology of PPHN
Elevated PVR in PPHN can be idiopathic/primary, secondary to lung disease (either parenchymal, alveolar space disease or pulmonary hypoplasia) or cardiac dysfunction.3 Normal cardiac physiology versus that of PPHN is shown in figure 1A–1D. Increased PVR leads to bidirectional or right-to-left shunting at the PFO and PDA and increases right ventricular (RV) afterload.4 The right-to-left shunting at the PFO reduces RV preload. The RV afterload can be transiently reduced by a right-to-left PDA shunt if the ductus remains open. Initial increases in afterload cause RV hypertrophy and increases contractility; however, persistent and excessive elevation of PVR is associated with myocardial stretching, ischaemia, hypoxaemia and acidosis, leading to RV dysfunction (table 1).5 Left ventricular (LV) dysfunction can lead to pulmonary venous hypertension and increase pulmonary arterial pressure and reduce systemic output. LV preload decreases secondary to low pulmonary venous return and/or bulging of the interventricular septum to the left. Additionally, hypoxaemic respiratory failure can be a primary driver for LV dysfunction. Abnormal interaction between the two ventricles, ischaemia, hypoxaemia and metabolic acidosis contribute to LV dysfunction.4 LV dysfunction can also exacerbate and lead to inhaled nitric oxide (iNO)-resistant PPHN by increasing pulmonary venous hypertension.6 Arteriovenous malformations—commonly either intracranial (vein of Galen malformation) or hepatic—can present with PPHN and systemic hypotension and should be included in the differential diagnosis.7–9 Rarely, the clinical characteristics (phenotypes) of PPHN can be mimicked in situations with normal PVR and reduced SVR due to conditions such as sepsis.10 11
Cardiac function and shunt changes in persistent pulmonary hypertension of the newborn (PPHN) (see figure 1)
Cardiac pathophysiology in PPHN. (A) A normal postnatal heart has L-to-R shunting at PFO and PDA with the IVS bulging to R. (B) In mild-to-moderate PPHN, the IVS can be midline with bidirectional shunts at PFO/PDA. Increased RV afterload is compensated by increased RV contractility. High-velocity tricuspid regurgitation is observed. (C) In severe PPHN, the PFO and PDA shunt R-to-L with IVS bulging to L, decreasing LV preload. Extremely high RV afterload leads to uncoupling of RV function leading to RV dilation. An open PDA might benefit the RV by providing a pop-off mechanism to reduce RV afterload. (D) When severe PPHN is associated with LV dysfunction, pulmonary venous hypertension and high pressure in the LA leads to L-to-R shunt at PFO but R-to-L shunt at PDA. Inhaled nitric oxide, as well as other therapies that lower pulmonary vascular resistance, can precipitate pulmonary oedema in pulmonary venous hypertension if LV failure or other forward flow obstructions are present. In the setting of LV dysfunction, postductal systemic perfusion is supplemented by a transductal R-to-L shunt. Copyright Satyan Lakshminrusimha. IVS, intraventricular septum; L, left; LV, left ventricular; PDA, patent ductus arteriosus; PFO, patent foramen ovale; PPHN; persistent pulmonary hypertension of the newborn; R, right; RV, right ventricular.
Normal blood pressure
The optimal systemic blood pressure during management of PPHN is not clear. There are several studies evaluating normal systemic systolic, diastolic and mean pressure during the first week after birth in term infants. Results from one such study are shown in table 2.12 However, instead of exclusively focusing on blood pressure numbers, the clinician should look for signs of hypoperfusion (figure 2).
Normal range of systemic blood pressure in mm Hg in term infants (numbers in parentheses are 2 SDs below the mean; these can be considered the lower limit of normal during pulmonary hypertension of the newborn management)
Assessment of perfusion: clinical signs such as mental status (consciousness), capillary refill, blood pressure and urine output coupled with pulse oximetry, perfusion index, pleth variability index, targeted bedside echocardiography, electrocardiography, NIRS and invasive monitoring with blood gas and lactate should be collectively interpreted to assess perfusion. Copyright Satyan Lakshminrusimha. HR, heart rate; NIRS, near-infrared spectroscopy; SVC, superior vena cava.
Haemodynamic assessment: flow, perfusion versus pressure
Systemic blood pressure and heart rate are the most commonly used parameters for assessment of systemic perfusion. However, blood pressure does not correlate well with perfusion in neonates. Mean and diastolic pressures correlate poorly with LV output.13 Pulse pressure and, to a less extent, systolic blood pressure correlate better with LV output.13 Clinical signs such as mental status, capillary refill and urine output are compromised during late phases of systemic hypoperfusion. Non-invasive monitoring of Perfusion Index, Pleth Variability Index, pulse oximetry (SpO2) and near-infrared spectroscopy can detect changes in systemic perfusion.14 Blood gas analysis and serum lactate are invasive mechanisms to assess systemic perfusion. In the last decade, bedside targeted neonatal echocardiography has become a popular mode of haemodynamic assessment.15
Causes of systemic hypotension in PPHN
Low SVR and systemic hypotension requiring treatment are common in infants with PPHN. Two-thirds of infants with PPHN requiring ventilation and 87% of infants requiring extracorporeal life support (ECLS) are on three or more inotropes.16 The aetiology of hypotension in PPHN is summarised in table 3 and figure 3.
Aetiology of systemic hypotension in persistent pulmonary hypertension of the newborn
Aetiology of systemic hypotension in PPHN. See table 3 for details. Copyright Satyan Lakshminrusimha. PDA, patent ductus arteriosus; PPHN, persistent pulmonary hypertension of the newborn; PVR, pulmonary vascular; Qp, pulmonary flow.
Fluid management
Many infants with systemic hypotension and PPHN receive fluid boluses prior to initiation of vasoactive agents.16 The relationship between intravascular blood volume and blood pressure is not clear in neonates.17 Additionally, the mechanism of hypotension in PPHN is often not due to hypovolaemia. In fact, routine administration of fluid boluses to an infant with PPHN without clinical evidence of hypovolaemia may potentially further exacerbate RV failure. Thus, fluid bolus administration should be targeted and administered only if there are other indications of hypovolaemia, such as low central venous pressure, documented excessive losses or concerns for increased insensible losses.
Vasoactive infusions
If the hypotension or poor perfusion does not appear to be due to hypovolaemia, vasoactive infusions are commonly initiated. The goal of vasoactive therapy is to improve oxygen delivery and perfusion (figure 4). The use of vasoactives to increase systemic blood pressure to supraphysiological levels (higher than the means shown in table 2) to minimise right-to-left shunt is not appropriate. Such practice increases RV afterload and hastens RV failure.18 Also, in the setting of LV dysfunction, postductal systemic perfusion is supplemented by a transductal right-to-left shunt. Additionally, if an infant appears to have evidence of adequate oxygen delivery (ie, normal lactate, normal urine output, no lethargy and without evidence of end-organ injury), despite having hypotension, then tolerating permissive hypotension may be appropriate. It is important to focus on evaluation and correction of hypoperfusion and not manage blood pressure numbers during management of PPHN.
Vicious cycle of pulmonary hypertension, systemic hypotension and cardiac dysfunction in PPHN. Selective pulmonary vasodilators to treat pulmonary hypertension, selective systemic vasoconstrictors to treat systemic hypotension and/or reducing afterload/optimising preload are important strategies to interrupt this vicious cycle. Modified from an unpublished e-review by Dany Weisz, Patrick McNamara and Amish Jain. Copyright Satyan Lakshminrusimha. LV, left ventricular; PDA, patent ductus arteriosus; PFO, patent foramen ovale; PPHN, persistent pulmonary hypertension of the newborn; RV, right ventricular.
Several vasoactive medications may be useful to treat hypotension associated with PPHN in neonates. All vary in mechanisms of action (figure 5) and may provide benefit or harm in different physiological circumstances. For example, vasoactive infusions can have the following effects: inotropy (heart contractility), chronotropy (heart rate), lusitropy (heart relaxation), vasoconstriction (or vasopressors) and/or vasodilation. Some vasoactive medications have more than one effect, and the effects can vary depending on dose. Understanding the physiology behind the neonate’s hypotension and the medication’s mechanism of action is necessary to choose the best treatment. A synopsis of each medication is provided in tables 4–11 and in figure 6.
Mechanism of action of vasoactive medications in vascular smooth muscle (brown-top) and endothelial cell (pink-bottom). V1R and V2R and vasopressin receptors. ET-A and ET-B are endothelin receptors. α1, α2, β1 and β2 are adrenergic receptors. Most of the vasoconstrictor mediators result in increase in cytosolic ionic calcium concentrations in the smooth muscle. Vasopressin (through V1 receptors), endothelin (through ET-B receptors) and norepinephrine (through α2 receptors) can act on pulmonary endothelium and stimulate NO production, leading to pulmonary vasodilation. Copyright Satyan Lakshminrusimha. eNOS, endothelial nitric oxide synthase; cAMP, cyclic adenosine monophosphate; IP3, inositol triphosphate; NO, nitric oxide; PDE3, phosphodiesterase 3; PLC, phospholipase C; sGC, soluble guanylyl cyclase; cGMP, cyclic guanosine monophosphate; SR, sacroplasmicreticulum.
Dopamine
Norepinephrine
Epinephrine
Dobutamine
Milrinone
Levosimendan
Vasopressin
Hydrocortisone
Vasoactive agents and their receptor distribution and action in various systems. Dopamine is a precursor of norepinephrine. Norepinephrine is converted to epinephrine by PNMT. Dopamine has a dose-dependent effect on dopamine (D1 and D2) receptors, β1 and α1 receptors. Epinephrine is equally effective on β1 and α1 receptors. Norepinephrine predominantly acts on α1 receptors causing systemic vasoconstriction. It is thought to stimulate α2 receptors in pulmonary vascular endothelium and release no leading to pulmonary vasodilation. Milrinone and levosimendan increases cardiac contractility. Vasopressin acts on V1 receptors to induce systemic vasoconstriction, V2 causing fluid retention in the kidneys and V3 leading to pituitary stimulation to produce adrenocorticotropic hormone (ACTH). vasopressin also stimulates pulmonary vascular endothelial V1 receptor and pulmonary vascular smooth muscle V2 receptor to induce pulmonary vasodilation. Copyright Satyan Lakshminrusimha. NO, nitric oxide; PDA, patent ductus arteriosus; PNMT, phenylethanolamine methyl transferase; PA, pulmonary artery.
Dopamine
Dopamine has conventionally been the first-line therapy for hypotension in neonates, including management of septic shock.19 However, its non-specific mechanism of action and effects on pulmonary versus systemic circulatory system has special implications in PPHN. Dopamine is a central neurotransmitter and is also a precursor to norepinephrine. It directly stimulates D1 and D2 receptors and directly (or through metabolism to norepinephrine) stimulates α1, β1 and β2 receptors. Therefore, dopamine can result in vasoconstriction, vasodilation, inotropy and/or chronotropy, depending on the dose.20 Additionally, the effect dopamine has on systemic versus pulmonary circulation varies with dose.21 For example, in a neonatal lamb model, dopamine selectively increased systemic arterial pressure at lower doses without significantly increasing pulmonary arterial pressure, thus increasing pulmonary blood flow in lambs without PPHN.2 However, in lambs with PPHN, the pulmonary vasculature is remodelled and pulmonary arterial pressure is more sensitive to vasoconstrictor effects of dopamine, and therefore dopamine did not increase pulmonary blood flow.2
In human neonates, the varying effect of dopamine on pulmonary arterial pressure has also been shown.21 In a study of 18 preterm newborns, the ratio of pulmonary/systemic arterial pressure increased (a preferential increase in pulmonary arterial pressure) in half of the newborns.21 This same study demonstrated changes in direction of blood flow across the PDA. After dopamine initiation, 2 of 11 newborns had PDA flow change from initially left-to-right to bidirectional shunting, suggesting further elevation of PVR.21 Thus, in a newborn with PPHN requiring dopamine infusion, monitoring of the directionality of PDA flow and pulmonary arterial pressure with serial echocardiograms is necessary.
Norepinephrine
Norepinephrine is more selective than dopamine with regard to receptor stimulation, acting primarily on α1 receptors, resulting in vasoconstriction and minimal inotropic effect on β1 receptors. The vasoconstriction mechanism could affect both systemic and pulmonary arterial pressures. Interestingly, fetal lamb models have shown norepinephrine may decrease the basal pulmonary vascular tone through stimulation of α2 receptors and nitric oxide (NO) release.22 In newborns with PPHN, norepinephrine has been shown to increase pulmonary arterial pressure; however, unlike dopamine, the ratio of pulmonary to systemic arterial pressure decreased following norepinephrine infusion (0.98 to 0.87, p<0.001).23 This study also noted decreased oxygen requirement and increased postductal oxygen saturation, supporting the notion of increased pulmonary blood flow following norepinephrine infusion.23
Epinephrine
Epinephrine is less selective than norepinephrine, and its stimulation on α and β receptors vary by dose. At lower doses, epinephrine has a predominant β effect causing chronotropy and inotropy. Thus, for an infant with depressed myocardial function, epinephrine may be useful. In paediatric trials, epinephrine has been shown to be superior to dopamine with faster resolution of shock and lower mortality.24 25 However, in neonatal trials, epinephrine and dopamine were comparable.26 27 However, epinephrine was associated with more metabolic disturbances such as hyperglycaemic and lactic acidosis.26
Dobutamine
Dobutamine is predominantly a β1 agonist resulting in significant inotropic effect. Thus, it may be useful for neonates with decreased cardiac function. However, the potential chronotropic effect must be considered. In a review of dobutamine, neonatal studies noted increased heart rate for all doses evaluated (5, 10 and 20 mcg/kg/min—studies of 2.5 and 7.5 mcg/kg/min did not report on heart rate).28 Studies also noted both increase and decrease in PVR with dobutamine.28 Specifically in neonates, a study among premature infants with depressed myocardial function noted a decreased fraction of inspired oxygen (FiO2) following dobutamine initiation, potentially reflecting increased pulmonary blood flow.29 Additionally, studies have shown dobutamine improves and maintains systemic blood pressure better than dopamine and with less LV stress.30 31 While dobutamine is predominately a β1 agonist, it is also a mild β2 and α1 agonist. The β2 effects of dobutamine are thought to reduce SVR; however, the reduction in SVR is more likely due to sympathetic withdrawal once cardiac function has improved. The overall net effect is expected to be significant inotropy, such that the other effects of dobutamine are likely trivial in comparison. However, it is most suitable for patients with LV dysfunction as the primary or major contributing factor leading to poor perfusion.
Milrinone
Milrinone is a phosphodiesterase 3 inhibitor which results in increased levels of cyclic adenosine monophosphate (cAMP). The increase in cAMP results in inotropic effect on myocardium and vasodilation, which may benefit neonates with PPHN and impaired myocardial function. In neonatal lambs, milrinone resulted in relaxation of pulmonary arteries in both controls and lambs with PPHN.32 In a study of 11 newborns with PPHN, milrinone has been shown to improve PaO2 and reduce FiO2, iNO and mean airway pressure needs—suggesting improved pulmonary blood flow.33 Additionally, while the newborns experienced a transient decrease in systemic arterial pressures, overall haemodynamics improved, as noted by decreased lactic acid and a trend towards decreased inotropic score.33 However, this study excluded infants with systemic hypotension.33 The systemic vasodilator effects of milrinone need to be considered, particularly in the setting of PPHN. Additionally, studies have generally only evaluated outcomes during the first 72 hours of milrinone initiation. Thus, while it is likely safe for longer administration, the effects beyond this in patients with PPHN are unknown.33 34 There are current two multicentre trials under way evaluating the use of milrinone in congenital diaphragmatic hernia (CDH)35 and PPHN.36
Levosimendan
See the Web (online supplemental appendix) for levosimendan details.
Supplemental material
Vasopressin
There are three subtypes of vasopressin receptors, V1–3. V1 receptors are located in the vasculature beds and are commonly known for their potent vasoconstrictive properties on systemic vasculature with minimal increase/decrease in PVR, leading to a decrease in the pulmonary/systemic arterial pressure ratio.37 The mechanism of vasodilation in the pulmonary vasculature is thought to be from stimulation of oxytocin endothelial receptors and subsequent NO pathway activation.38 Siehr et al evaluated three vasoactive medications (phenylephrine, vasopressin and epinephrine) in 15 paediatric patients with pulmonary hypertension, and vasopressin was the only infusion that consistently decreased the pulmonary/systemic arterial pressure ratio.37
Specifically in newborns, Mohamed et al reported a case series of newborns with PPHN in which vasopressin was used as a ‘rescue’ therapy for refractory pulmonary hypertension and systemic hypotension despite iNO and vasoactive infusions.39 In this series, vasopressin resulted in improved oxygenation index and reduced iNO.39 Three of the 10 newborns were also receiving milrinone. However, the improvement in oxygenation index persisted when excluding the newborns that received milrinone from the analysis.39 However, it is notable that 4 of the 10 newborns died, and 2 required ECLS, which may reflect their severity of illness at the time vasopressin was initiated as a rescue therapy in this series.39 Acker et al reported a case of 13 newborns with CDH that received vasopressin for refractory hypotension. All 13 newborns in this series met ECLS criteria prior to vasopressin initiation. Eleven patients received vasopressin prior to initiation of ECLS (the other two received vasopressin concurrently with ECLS initiation). In 6 of those 11 patients, ECLS was no longer indicated due to overall improved haemodynamics.40 In both the Acker et al and Mohamed et al series, vasopressin was used essentially as a rescue therapy after other interventions failed. Thus, earlier initiation of vasopressin in newborns with pulmonary hypertension warrants additional research.
However, it is notable that prior studies did not elaborate on the mechanism of hypotension in the newborns that received vasopressin. Assumingly, when considering its mechanism of action, vasopressin could be beneficial for a patient with low SVR and good LV function and potentially harmful for a newborn with poor LV dysfunction by increasing SVR (or LV afterload). Contrary to this assumption, low dose vasopressin has been beneficial in the postoperative management of newborns following the Norwood procedure or arterial switch operation (less fluid resuscitation needs and lower inotropic scores in the first 24 hours in the vasopressin group).41 The low cardiac output state of these newborns is multifactorial, but likely involves some degree of LV dysfunction. The lack of deleterious effects from vasopressin in these situations may be related to improved coronary perfusion.42 Nonetheless, more information on the pathophysiology of newborns with PPHN treated with vasopressin will be useful in future studies to help better determine situations in which it should be used.
The effect vasopressin has on sodium and water balance has to be considered prior to initiation. Vasopressin can alter sodium and water balance via two mechanisms—V1 receptors result in peripheral vasoconstriction and thus improved renal blood flow, and V2 receptors have antidiuretic effects resulting in reabsorption of free water. This last mechanism has the potential to cause hyponatraemia. In the Acker et al series, they reported hyponatraemia complications for the newborns that did not require ECLS, which they explain was due to differences in vasopressin doses used in the two groups. All six of the newborns experienced a decrease in serum sodium (average nadir 117.8 mmol/L, range 111–121) and were also treated for hyponatraemia.40 Mohamed et al reported ‘negligible change in serum sodium’ among their newborn series.39 The degree of shock and mechanism of shock likely impacts the effect vasopressin has on sodium balance. For example, a review noted minimal or no cases of hyponatraemia among studies of adults and children when vasopressin was used in settings of vasodilatory shock; however, hyponatraemia was commonly noted when vasopressin was used for indications other than vasodilatory shock.43 Nonetheless, use of vasopressin in neonates requires monitoring of serum sodium, and research evaluating the effect on serum sodium at varying doses and varying clinical indications in neonates may be helpful.
Hydrocortisone
Corticotrophin-releasing hormone (CRH), the hypothalamic peptide regulating the hypothalamus–pituitary–adrenal axis in response to stress, is expressed in abundance in the human placenta and contributes to fetal cortisol during late gestation.44 This source of CRH is lost following birth. Late preterm and term infants requiring vasopressor support have low cortisol levels but a normal response to exogenous ACTH.45 Randomised trials to evaluate cortisol in term infants are warranted but are difficult to conduct.46 47 The optimal indication and dose of hydrocortisone in neonatal hypotension is not clear.46 47 However, cases demonstrating response to exogenous glucocorticoids in catecholamine-resistance hypotension are reported.48
The mechanisms of cardiovascular effects of hydrocortisone administration are not completely understood, but both genomic and nongenomic steroidal effects seem to play a role.49 Hydrocortisone administration to preterm and term infants with vasopressor-resistant hypotension is associated with an improvement in BP, stoke volume (and a trend to increase in cardiac output) with a decrease in heart rate and need for vasoactive medications.49 Genomic upregulation of cardiovascular adrenergic and angiotensin receptors and inhibition of inducible NO synthase and prostaglandins are potential mechanisms. In addition, non-genomic effects such as better capillary integrity, inhibition of catecholamine metabolism and increase in intracellular calcium may be mainly responsible for the rapid onset of the hydrocortisone-induced BP improvement.49
In addition to increasing blood pressure, glucocorticoids might have an effect on the lung in PPHN. Glucocorticoids may have beneficial effects in meconium aspiration syndrome,50 but there is a concern of exacerbation of infection and lack of multicentre randomised trials.51 Animal studies have shown that high-dose hydrocortisone inhibits phosphodiesterase 5 enzyme and enhances oxygenation response in PPHN.52 53 A single-centre case series using 4 mg/kg loading dose followed by 1 mg/kg/dose every 6 hours in PPHN resistant to conventional therapy showed significant improvement in oxygenation and blood pressure with a reduction in the need for vasopressors.54
Special considerations
Infants born to mothers with diabetes may have hypertrophic cardiomyopathy and impaired cardiac output that must be considered when choosing vasoactive medications. See the Web (online supplemental appendix) for more.
Extracorporeal life support
ECLS is a treatment option for newborns with PPHN, of which more information is in the Web (online supplemental appendix).
Conclusion
PPHN may be characterised by a multitude of physiological imbalances such an increased PVR to SVR ratio, or due to LV dysfunction or increased pulmonary blood flow that results in increased pulmonary artery pressure. Systemic hypotension is extremely common among infants with PPHN and should be identified early. Systemic hypotension is almost invariably a component of the clinical syndrome of PPHN but may have a variety of mechanisms that require thoughtful and targeted assessment and therapy. Further trials evaluating various vasoactive agents in PPHN are warranted.
Data availability statement
No data are available. A review article with no data.
Ethics statements
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @neosatyan
Funding HMS’s effort was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH) (through grant UL1 TR001860 and linked award KL2 TR001859) and by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH (1R21 1HD099239-01). Dr Lakshminrusimha was supported by NICHD and NIH (5R01 HD072929-09). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the NIH.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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