Treatment and Prevention of Post-dural Puncture Headaches: A Systematic Review

Post-dural puncture headache (PDPH) is occasionally an inevitable side effect of neuraxial anesthesia, which can happen after spinal anesthesia or if an accidental dural puncture (ADP) happens during epidural anesthesia. The treatment and prevention options for PDPH differ widely from one institution to another. The management of PDPH is heterogeneous in many institutions because of the absence of clear guidelines and protocols for the management of PDPH. This study aimed to summarize all articles published during the past decade that discussed the treatment or prevention of PDPH. From 2013 to 2023, 345 publications were filtered for all treatment and prevention approaches used for PDPH patients. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines were followed for conducting this systematic review, and 38 articles were included for analysis and review. Existing data come from small randomized clinical trials and retrospective or prospective cohort studies. This review supports the effect of oral pregabalin and intravenous aminophylline in both treatment and prevention. Intravenous mannitol, intravenous hydrocortisone, triple prophylactic regimen, and neostigmine plus atropine combination showed effective and beneficial outcomes. On the other hand, neither neuraxial morphine nor epidural dexamethasone showed promising results. Consequently, the use of neuraxial morphine or epidural dexamethasone for the prevention of PDPH remains questionable. Regarding the posture of the patient and its consequences on the incidence of the headache, lateral decubitus is better than a sitting position, and a prone position is better than a supine position. Smaller non-cutting needles play a role in avoiding PDPH. Minimally invasive nerve blocks, including sphenopalatine ganglion or greater occipital nerves, are satisfyingly effective. Epidural blood patches remain the more invasive but the gold standard and ultimate solution in patients resisting medical therapy. This study highlights the need for larger research to define the best approach to prevent and treat PDPH.


Introduction And Background Definition, risk factors, and clinical presentation
In the third edition of the International Classification of Headache Disorders (ICHD-3), the Headache Classification Committee of the International Headache Society (HIS) defines post-dural puncture headache (PDPH) as a headache developing within five days after a lumbar puncture and is attributed to cerebrospinal fluid (CSF) leakage through a dural hole, associated usually with a stiff neck and/or hearing symptoms [1].Remission is spontaneous within two weeks if left untreated or after the sealing of the leak by an epidural blood patch (EBP) [1].PDPH is a serious side effect of neuraxial anesthesia, which can happen after spinal anesthesia or if an accidental dural puncture (ADP) happens during epidural anesthesia.Female gender, youth, pregnancy, vaginal delivery, having a low body mass index, and not smoking are risk factors [2].Patients with PDPH typically present with frontal or occipital headaches radiating to the neck or shoulder area within six to 72 hours of the procedure.The headache gets worse in an upright position and relieves in a supine position [2][3][4].Nausea, vomiting, dizziness, tinnitus, stiff neck, and visual abnormalities are possible associated symptoms [5].

Incidence
The rate of unintentional puncture of the dura mater during epidural placement is 1.5% (95% CI: 1.5-1.5%),and over half of these patients (52.1%; 95% CI: 51.4-52.8%)experience PDPH [6].Additionally, 76-85% of patients may develop PDPH according to a more recent study [7].However, PDPH is more frequently caused by dural puncture during epidural anesthesia than by spinal anesthesia because spinal anesthesia uses small, pencil-point needles.When a pencil-point spinal needle is used, the risk of PDPH is reduced [2].The risk of PDPH can be influenced by the size, shape, and orientation of the spinal needles, as well as the patient's posture [4].
CSF is a clear fluid produced in the choroid plexus inside the ventricles of the brain and reabsorbed by arachnoid granulations of the arachnoid matter into the bloodstream [3].The average CSF volume in an adult is 150 mL, filling the cranial and spinal cavities [3].If there is CSF leak as a consequence of a dural perforation significant enough to exceed CSF production, the CSF pressure will drop, and CSF hypotension occurs [3].It is expected that, if more than 10% of the total CSF volume is lost, orthostatic headache will develop [3].There are two proposed mechanisms explaining how headaches are brought on by CSF hypotension.The sagging theory claims that, when the patient takes an upright position, the reduced volume of CSF will be pulled down and shifted from the cranial cavity to the vertebral canal [3].Hence, the brain sags into the foramen magnum with the meninges and cranial nerve being pulled consecutively [3].This theory explains the symptoms of cranial nerve palsies seen in some patients with PDPH [3].The second proposed theory states that cerebral vasodilation, which will occur to compensate for CSF loss and to maintain a constant total intra-cranial volume, is the reason for the headache [3].
The treatment and prevention options for PDPH differ widely from one institution to another [8].The management of PDPH is heterogeneous in many institutions because of the absence of clear guidelines and protocols for the management of PDPH [8].The currently available treatment options in the literature are bed rest, acetaminophen, caffeine, pregabalin, aminophylline, hydrocortisone, mannitol, neostigmine plus atropine, cosyntropin, sphenopalatine ganglion and greater occipital nerve blocks, and the more invasive EBP [3,8,9].The greater occipital nerve supplies the skin over the posterior scalp up to the coronal suture.This nerve can be blocked medial to the occipital artery and lateral to the nuchal midline.Greater occipital nerve block will omit sensation from skin, muscles, and vasculature over the posterior side of the head [3].The sphenopalatine ganglion is composed of sympathetic, parasympathetic, and sensory fibers [3].It is located in the posterior nasal pharynx in the pterygopalatine fossa [3].It can be blocked trans-nasally using cotton-tipped applicators soaked in lidocaine [3].EBP has been suggested to be a useful treatment for severe or incapacitating PDPH, as well as a preventive measure for high-risk individuals.However, due to its invasiveness, requirement for anesthesiologists, and doubtful effectiveness, there are a number of issues with its application [5].The incidence can be greatly decreased by paying attention to procedure-related factors.The position of the patient during the procedure and the size and shape of the needle all seem to play a role in the prevention of PDPH.
Subdural hematoma, diplopia as a result of cranial nerve palsy, cerebral venous thrombosis, chronic headache, and post-partum depression have been reported as complications of unintentional dural puncture (UDP) [3].PDPH is occasionally an inevitable side effect.As a result, anesthesiologists must understand prevention and treatment strategies.This study aimed to summarize all articles published during the past decade that discussed the treatment or prevention of PDPH.

Review Methods
We followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2020 guidelines for conducting this systematic review [10].PubMed and ScienceDirect were explored for studies published between 2013 and 2023.The search strategy included the following keywords: ((post-dural puncture headache [Title/Abstract]) AND (treatment [Title/Abstract])).The search strategy was not limited by geographical criteria.Only English-language articles were reviewed for inclusion.Both peer-reviewed experimental and observational studies were included.After the identification process, two independent coauthors screened the information from the publications based on the title and abstract.The initial analysis of the two databases resulted in 345 publications.After further elimination according to the below criteria, a total of 38 were found that covered the aim of this review.

Inclusion Criteria
This review included full-text publications that focused on treatment and/or preventive measures of PDPH, published between 2013 and 2023 and written in English.

Exclusion Criteria
Review articles, case reports, and case series were not considered.Duplicate articles were excluded.The inclusion and exclusion methods of this review are shown in Figure 1.(2018) [12] India A retrospective analysis (n=407) All patients were given pharmacological treatment.71% of patients were either on coffee or caffeine tablets.One case of persistent PDPH showed a good response to oral pregabalin 75 mg.
PDPH can be effectively controlled with drug treatment only.did not (group 2).Upon comparing the outcome between the two groups, there was no significant difference regarding the incidence of headaches nor the need for EBP or the headache intensity.Furthermore, the morphine group had a higher hospital length of stay.
Neuraxial morphine may not have a preventive role against the risk of PDPH in cases of ADP.Peralta et al.
(2020) [24] USA A randomized double-blind trial (n=61) No differences were documented between groups regarding the onset, duration, severity of headache, or presence of cranial nerve symptoms.The incidence of PDPH in the intrathecal morphine group was 78%, and 79% in the intrathecal saline group.
This research challenges the efficacy of prophylactic intrathecal morphine after accidental dural puncture.The group of patients who had SPG block had significantly lower headache pain scores and less total paracetamol consumption.furthermore, a markedly better satisfaction score was reported in the study group.
One patient in the control group needed an epidural blood patch.
SPG block is a good alternative in treating PDPH. the requirement for an epidural blood patch is markedly reduced with the implication of SPG block.
Fast and sustained pain relief as well as procedural safety make it an evolving management for PDPH.

Pharmacological Treatment
This systematic review identified 16 publications assessing medical drugs for the treatment and prevention of PDPH [9,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].According to a retrospective assessment of medical records that included 285 patients and was published in 2013, analgesics and antiemetics, along with bed rest and IV fluids, were sufficient to manage the symptoms of PDPH in about 79% of patients [11].Another retrospective assessment of 407 cases concluded that PDPH can be effectively controlled with drug treatment only, mostly caffeine tablets [12].Among antiepileptic medications, gabapentin and pregabalin are well-known to play a role in pain alleviation for patients with PDPH.Three randomized control studies investigated the role of antiepileptic drugs in the treatment or prevention of PDPH [13][14][15].In one Irani study, the researchers compared the effect of pregabalin, gabapentin, and acetaminophen in patients with PDPH.Interestingly, the visual analog scale (VAS) score was the highest in the acetaminophen group than in the gabapentin group and the lowest in the pregabalin group, concluding that pregabalin is the most effective medication in that trial [13].The remaining two trials discussed the prevention of PDPH [14,15].Oral pregabalin administered one night before spinal anesthesia was associated with a decreased incidence of PDPH compared to placebo [14].On the other hand, pre-operative gabapentin had no significant effect on the incident in an Egyptian study; however, its beneficial effect in reducing the severity and the duration, as well as delaying the onset of the headache, was reported [15].
Intravenous aminophylline is successful in both treatment and prevention of PDPH [16][17][18][19].In one study, the combination of 0.1 mg/kg of dexamethasone and 1.5 mg/kg of aminophylline enhanced the effect of aminophylline when compared to dexamethasone alone and aminophylline alone [19].The role of dexamethasone alone in the treatment or prevention of PDPH seems to be questionable.A clinical trial published in 2014 denied the prophylactic effect of epidural dexamethasone in PDPH cases as there was no statistical difference between cases and controls [20].However, in a more recent paper published in 2022, there was an association between intravenous dexamethasone administration and better outcomes in pain alleviation compared to placebo [16].
Mannitol intravenously was shown to be more effective in treating PDPH than acetaminophen-caffeine capsules when these two methods were compared in a randomized clinical trial published in 2021 [21].In another trial, intravenous mannitol was compared to intravenous hydrocortisone, which concluded that both medications are equally effective in pain relief; however, hydrocortisone had earlier onset [9].
The benefit of a triple prophylactic regimen consisting of epidural saline, morphine, and intravenous (IV) cosyntropin was evaluated in an observational study published in 2020 [22].The group of patients who received a triple prophylactic regimen was compared to a group that received conservative measures, including oral paracetamol, oral ibuprofen, oral opioid-containing formulations, and intravenous caffeine.The triple prophylactic regimen succeeds in decreasing the rate of PDPH and the demand for blood patches.This was not the situation when morphine was administered alone intrathecally.In fact, two papers investigated the effectiveness of intrathecal morphine in reducing the incidence of headache after accidental dural puncture; in both papers, no statistically significant difference was documented between the study group and control group [23,24].As a result, the clinical usefulness of neuraxial morphine in the prevention of PDPH is not supported by these findings [23,24].
A very recent clinical trial published in 2023 concluded that the combination of 40 μg/kg neostigmine plus 20 μg/kg of atropine is greatly effective in reducing the frequency of PDPH and the need for medical treatment to control the headache after spinal anesthesia [25].Neostigmine is widely used in anesthesia practice as a reversal of the effect of non-depolarizing muscle relaxants.It is a quaternary amine cholinesterase inhibitor that increases CSF secretion.Despite the fact that anti-choline esterase drugs generally increase levels of acetylcholine in neuromuscular junctions, and acetylcholine decreases CSF secretion in choroid plexuses, neostigmine competes with acetylcholine in entering the choroid plexus, which will the lower acetylcholine level and increase CSF secretion eventually [25].Additionally, neostigmine is thought to be a cerebral vasoconstrictor by directly stimulating cerebrospinal ganglia, and this counteracts cerebral vasodilatation in PDPH and could be a possible explanation of the preventive effect of neostigmine in patients with PDPH.The beneficial effect of atropine in cases with PDPH can be explained by two actions, increasing CSF secretion by blocking the acetylcholine effect and cerebral vasoconstriction by the inhibition of sphenopalatine ganglion [25].

Position of the Patient
Spinal anesthesia can be administered in the sitting, lateral decubitus, or even prone position.Needless to say, each position has its own advantages and disadvantages.Besides all the previously mentioned factors that could influence the occurrence of PDPH, the position of the patient during the procedure influences the occurrence of PDPH as well [26].Two recent papers published in 2022 discussed the impact of the posture on the incidence of PDPH [26,27].The lateral decubitus position was shown to be better than the sitting position as it was associated with a lower incidence of PDPH [26].A cohort study with a total of 1,416 patients compared between prone and supine position regarding the frequency of PDPH after the operation [27].Moreover, 0.68% of the patients in the prone position group complained of having PDPH, whereas 8.95% of patients in the supine group experienced PDPH, concluding that the prone position is associated with a lower incidence of PDPH when compared to the supine position.

Needle Factors
We found three published papers evaluating the impact of the needle size on the incidence of headache after dural puncture and other associated complications [28][29][30].A study conducted in Denmark concluded that smaller non-cutting needles significantly decreased the incidence of PDPH, as well as the first operator's failure rate and the number of failed attempts [28].The usage of smaller non-cutting needles in spinal anesthesia was also associated with a decrease in hospital stays, the number of days off from work, and the need for blood patch treatment [28].A turkey study highlighted the benefit of a small diameter needle (less than 22 G) and the importance of avoiding multiple attempts in spinal anesthesia as it was linked to a lower incidence of headache after dural puncture according to their results [30].The third article assessed the clinical application and performance of a novel bioimpedance spinal needle system.The study included 152 intrathecal treatment lumbar punctures (LP) done for 50 pediatric patients with acute lymphoblastic leukemia (ALL) [29].The bioimpedance spinal needle system measures continuously the bioimpedance of tissues that are in immediate contact with the needle tip and gives an audio-visual alarm when the needle tip reaches CSF in the subarachnoid space [29].The incidence of PDPH was 6% during the first week after the procedure, and no major complications were documented in the representative sample, concluding that the novel bioimpedance spinal needle system has achieved a high success rate.The promising results indicate clinical utility for the system in pediatric haemato-oncology [29].

Epidural Blood Patch
A total of 1,001 patients with PDPH from 24 countries were enrolled in an international cohort study to describe the management practices in PDPH cases and the effectiveness of EBP [31].Variation was obvious between different countries regarding the management practices in cases of PDPH.However, EBP was the most chosen management in cases with higher initial headache severity [31].Many other publications showed the efficacy and wide application of EBP in the treatment and prevention of PDPH [32][33][34][35][36][37].A prospective study that began in 1997 and ended in 2005 declared that 18.3% of patients who received prophylactic EBP developed headaches eventually compared to 79.6% of the patient who did not receive EBP for prophylaxis, which highlights the preventive effect of EBP in PDPH cases [32].
Epidural infusion of hydroxyethyl starch (HES) was shown to have similar efficacy to prophylactic EBP in cases with unintentional dural puncture (UDP) [33].However, prophylactic EBP was superior to prophylactic epidural HES in reducing the length of hospital stays of patients with UDP [33].Three Korean retrospective studies compared the response to EBP between cases of PDPH and cases of spontaneous intracranial hypotension (SIH) [34][35][36].In all three papers, patients with SIH required more epidural blood patch treatments and more often needed repeated epidural blood patch treatments compared to patients with PDPH [34][35][36].The international normalized ratio (INR) was associated significantly with repeated EBPs in patients with SIH [36].INR values were found to be high in SIH patients with poor response to EBP.Contrarily, INR was not a significantly associated factor with repeated EBP requirements in cases with iatrogenic injury [36].However, patients with elevated INRs were not included in the study as they are not candidates for EBP due to the risk of complications such as hematoma formation.Thus, that paper cannot determine if improving the coagulation profile of patients will decrease the incidence of repeated EBPs [36].CSF leakage was another factor associated with repeated EBP requirements in the representative sample [36].Possible factors associated with failed EBPs are a shorter time between an accidental dural puncture and an epidural blood patch, as well as a higher lumbar level of the accidental puncture [37].A history of migraine increases the risk of a second EPB [37].

Fibrin Glue Application
The novel use of Tisseel (fibrin glue) showed promising results [38].A retrospective study included 199 patients matched to one of the two groups, with fibrin glue and without fibrin glue, and found that patients who received prophylactic fibrin glue had a shorter duration of symptoms than patients in the no-glue group [38].Its impact on PDPH, its safety profile, its affordable cost, and its reproducibility make it an efficient technique [38].

Nerve Block
We reached eight publications that discussed nerve block as a treatment or preventive measure in PDPH [39][40][41][42][43][44][45][46].An Egyptian randomized clinical trial demonstrated that sphenopalatine ganglion (SPG) block and greater occipital nerve block (GONB) are equally effective in the treatment of PDPH [39].Moreover, both approaches are less invasive and safer than EBP [39].Two Indian publications support SPG block as a good alternative modality in treating PDPH [40,41].A single-blinded randomized study highlighted that the applicator technique of a trans-nasal SPG block produces superior pain alleviation compared to the nasal spray approach [42].Contrarily, one trial revealed no significant difference between SPG block and placebo in terms of PDPH treatment [43].Three retrospective studies evaluated the efficacy of GONB in the treatment of PDPH [44][45][46].Ultrasound-guided GONB has shown to be a good option for patients not responding to conservative therapy and could be taken into consideration before the application of a blood patch [44][45][46].An Egyptian randomized controlled trial investigated the efficacy of injecting dexamethasone plus lidocaine in the suboccipital muscles to relieve the headache after spinal anesthesia in women undergoing cesarian section [47].The group of women who had ultrasound-guided injection of dexamethasone plus lidocaine in the suboccipital muscle reported lower headache scores compared to the control group at all the post-injection time points, concluding that this approach is effective in treating PDPH [47].

Limitations
Only a few publications covered each modality of PDPH management, although that paints a picture of the current protocol in managing PDPH, which was a goal.

Conclusions
PDPH is one of the most common complications of spinal anesthesia and accidental dural puncture during epidural anesthesia.This systematic review summarizes all articles published in the past decade that discussed the treatment or prevention of PDPH.Existing data come from small randomized clinical trials and retrospective or prospective cohort studies.This review supports the effect of oral pregabalin and intravenous aminophylline in both treatment and prevention.Intravenous mannitol, intravenous hydrocortisone, triple prophylactic regimen, and neostigmine plus atropine combination showed effective and beneficial outcomes.On the other hand, neither neuraxial morphine nor epidural dexamethasone showed promising results.Consequently, the use of neuraxial morphine or epidural dexamethasone for the prevention of PDPH remains questionable.Regarding the posture of the patient and its consequences on the incidence of the headache, lateral decubitus is better than a sitting position, and a prone position is better than a supine position.Smaller non-cutting needles play a role in avoiding PDPH.Minimally invasive nerve blocks including sphenopalatine ganglion or greater occipital are satisfyingly effective.Epidural blood patches remain the more invasive but the gold standard and ultimate solution in patients resisting medical therapy.Larger research is warranted to define the best approach to prevent and treat PDPH.

FIGURE 1 :
FIGURE 1: PRISMA 2020 flow diagram illustrating the inclusion and exclusion process.
patients were successfully managed with conservative therapies alone (bedrest, IV fluids, analgesics, antiemetics), on the other hand, 21% required progression to interventional therapies (epidural blood or fibrin glue patch procedures) for full resolution of symptoms.
group of 14 cases received triple prophylaxis, three patients developed PDPH (21%), with two of them requiring a blood patch (14%).The second group of nine patients who underwent measures different than triple prophylaxis had a PDPH rate of 55% and only one patient required a blood patch (11%).neuraxial morphine (group 1) and 42 The rates of PDPH were 84%, 52.6%, and 54.5% with conservative, prophylactic EBP, and prophylactic epidural hydroxyethyl starch (HES), respectively.Prophylactic EBP and prophylactic epidural HES therapy greatly reduced the incidence of PDPH when compared to the conservative treatment.Therapeutic EBP was utilized much less in the prophylactic EBP and prophylactic epidural HES groups than in the conservative therapy group.Prophylactic EBP considerably shortened the length of hospital stay while prophylactic epidural HES showed no statistical difference compared with conservative treatment.